Type III secretion system flagellar brake protein YcgR, PilZN domain
Type:
Domain
Description:
This entry represents the N-terminal domain of YcgR proteins, located N-terminal to PilZ domains, thus named PilZN domain (also known as YcgR domain) [
]. The function of this domain is not known, but it is known to interact with the C-terminal which has cyclic-di-GMP bound [
]. YcgR is involved in the flagellar motor function and is a member of the flagellar regulon [,
]. This domain exhibits a similar structure as PilZ domains comprising a β-barrel fold but lack the C-terminal α-helix [].
Signal transduction response regulator, phosphate regulon transcriptional regulatory protein PhoB
Type:
Family
Description:
Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions [
]. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk []. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more []. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) []. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [,
].This entry represents the signal transduction regulatory protein PhoB. PhoB is a DNA-binding response regulator protein acting with PhoR in a 2-component system responding to phosphate ion. PhoB acts as a positive regulator of gene expression for phosphate-related genes such as phoA, phoS, phoE and ugpAB as well as itself [
]. It is often found proximal to genes for the high-affinity phosphate ABC transporter (pstSCAB; ) and presumably regulates these as well.
Ankyrin repeat and SOCS box protein 7, SOCS box domain
Type:
Domain
Description:
ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence [
]. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system []. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 []. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.This entry represents the SOCS box domain of ASB7.
Ankyrin repeat and SOCS box protein 6, SOCS box domain
Type:
Domain
Description:
ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence [
]. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system []. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 []. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.This entry represents the SOCS box domain of ASB6.
Ankyrin repeat and SOCS box protein 5, SOCS box domain
Type:
Domain
Description:
ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence [
]. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system []. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 []. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.This entry represents the SOCS box domain of ASB5.
Ankyrin repeat and SOCS box protein 3, SOCS box domain
Type:
Domain
Description:
ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence [
]. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system []. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 []. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.This entry represents the SOCS box domain of ASB3.
Ankyrin repeat and SOCS box protein 2, SOCS box domain
Type:
Domain
Description:
ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence [
]. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system []. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 []. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.This entry represents the SOCS box domain of ASB2.
Ankyrin repeat and SOCS box protein 1, SOCS box domain
Type:
Domain
Description:
ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence [
]. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system []. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 []. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.This entry represents the SOCS box domain of ASB1.
Ankyrin repeat and SOCS box protein 8, SOCS box domain
Type:
Domain
Description:
ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence [
]. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system []. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 []. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.This entry represents the SOCS box domain of ASB8.
Ankyrin repeat and SOCS box protein 9/11, SOCS box domain
Type:
Domain
Description:
ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence [
]. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system []. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 []. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.This entry represents the SOCS box domain of ASB9 and ASB11.
Ankyrin repeat and SOCS box protein 13, SOCS box domain
Type:
Domain
Description:
ASB (ankyrin SOCS box) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence [
]. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system []. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2 []. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.This entry represents the SOCS box domain of ASB13.
Growth arrest and DNA damage-inducible proteins-interacting protein 1 domain superfamily
Type:
Homologous_superfamily
Description:
This superfamily represents a domain found in proteins which act as negative regulators of G1 to S cell cycle phase progression by inhibiting cyclin-dependent kinases. Inhibitory effects are additive with GADD45 proteins but occur also in the absence of GADD45 proteins. Furthermore, they act as a repressor of the orphan nuclear receptor NR4A1 by inhibiting AB domain-mediated transcriptional activity [
]. They may be involved in the hormone-mediated regulation of NR4A1 transcriptional activity.Structurally, this domain consists of 4 alpha helices.
Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein
Type:
Family
Description:
ASAPs (ASAP1, ASAP2, and ASAP3) function as Arf-specific GTPase-activating proteins (GAPs), participate in rhodopsin trafficking, are associated with tumour cell metastasis, modulate phagocytosis, promote cell proliferation, facilitate vesicle budding, Golgi exocytosis, and regulate vesicle coat assembly via a Bin/Amphiphysin/Rvs domain [,
,
]. Each member has a BAR, PH, Arf GAP, Ank repeat and proline rich domains. ASAP1 and ASAP2 also have a SH3 domain at the C terminus []. The ASAP family is named for the first identified member, ASAP1 [].
S phase cyclin A-associated protein in the endoplasmic reticulum, N-terminal
Type:
Domain
Description:
This entry represents a short highly conserved region close to the N terminus of SCAPER. SCAPER is an ER-localised protein and a substrate for cyclin A/Cdk2. One theory suggests that SCAPER functions to create a local high concentration of cyclin A2 in the cytoplasm. Alternatively, SCAPER might be acting to sequester a portion of cellular cyclin A2 that could then be readily available for nuclear translocation, which may be needed for exit from G0 phase [
,
].
Interferon regulatory factor 2-binding protein 1/2, C3HC4-type RING finger superfamily
Type:
Homologous_superfamily
Description:
Interferon regulatory factor 2-binding protein 1 and 2 (IRF-2BP1/2) and their homologue IRF-2BP-like (also known as IRF-2BPL or C14orf4) () are nuclear transcriptional repressor proteins that bind to the C-terminal repression domain of IRF-2 and can inhibit both enhancer-activated and basal transcription. They contain N-terminal zinc finger and C-terminal RING finger domains [
,
,
]. Mutations in IRF2BP2 are responsible for a Familial Form of Common Variable Immunodeficiency Disorder (CVID), one of the most frequently diagnosed forms of primary immunodeficiency characterised by low quantity of IgG and IgA and poor specific antibody production []. IRF2BPL may play a role in the development of the central nervous system and in neuronal maintenance [].This superfamily represents the C-terminal C3HC4-type RING finger of IRF2BP1/2 and IRF2BPL [].
Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment superfamily
Type:
Homologous_superfamily
Description:
ATS is the intracellular and relatively conserved acidic terminal segment of the Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) [
]. This domain appears to be present in all variants of the highly polymorphic PfEMP1 proteins.
Bromodomain adjacent to zinc finger domain protein 2A, PHD zinc finger
Type:
Domain
Description:
Bromodomain adjacent to zinc finger domain protein 2A (BAZ2A, also known as TIP5 or WALp3) is an epigenetic regulator. It forms the nucleolar remodeling complex (NoRC) with ATPase SNF2h, which mediates silencing of a fraction of rDNA by recruiting histone-modifying enzymes and DNA methyltransferases, leading to heterochromatin formation and transcriptional silencing [
,
,
]. BAZ2A contains a TAM (TIP5/ARBP/MBD) domain, a DDT domain, four AT-hooks, BAZ 1 and BAZ 2 motifs, a WAKZ (WSTF/Acf1/KIAA0314/ZK783.4) motif, a plant homeodomain (PHD) finger, and a bromodomain. The C-terminal bromodomain, which is found in many chromatin-associated proteins and has been shown to bind to acetylated histone tails. The bromodomain cooperates with an adjacent PHD finger to recruit HDAC1, DNMT1, DNMT3, and SNF2h to rDNA [].This entry represents the PHD zinc finger of BAZ2A.
Regulator of G-protein signalling 2, regulator of G protein signaling domain
Type:
Domain
Description:
RGS2 is a member of B/R4 subfamily of RGS family, a diverse group of multifunctional proteins that regulate cellular signalling events downstream of G-protein coupled receptors (GPCRs) [
]. Signaling is initiated when GPCRs bind to their ligands, triggering the replacement of GDP bound to the G-alpha subunits of heterotrimeric G proteins with GTP. RGSs inhibit signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. This activity defines them as GTPase activating proteins (GAPs).
RGS2 blocks Gq-alpha mediated signalling [
]. It lacks Gs-alpha GAP activity, but can directly inhibit the activity of several adenylyl cyclase isoforms []. RGS2 is involved in the regulation of multiple G-protein linked signaling pathways. It plays a crucial role in the pathogenesis of cardiovascular diseases [,
].This entry represents the regulator of G protein signaling (RGS) domain found in RGS2. RGS shows an all-α structure [
,
].
Type VI secretion system spike protein VgrG2, domain of unknown function DUF2345
Type:
Domain
Description:
Type VI secretion system (T6SS) appears to be confined to Proteobacteria. It is important for bacterial pathogenesis, but it is also found in non-pathogenic bacteria, suggesting that T6SS involvement is not limited to virulence [
]. T6SS was identified in Vibrio cholerae [] and Pseudomonas aeruginosa [], and exports Hcp (Haemolysin-Coregulated Protein) and a class of proteins named Vgr (Val-Gly Repeats). In addition to Vgr and Hcp proteins, T6SS is characterised by the presence of an AAA+ Clp-like ATPase and of two additional genes icmF and dotU, encoding homologues of T4SS stabilising proteins []. Type VI secretion system spike protein VgrG2a and VgrG2b are homologous to (gp27)3-(gp5)3 phage-tail proteins, which is followed by a domain of unknown function (DUF2345). Unlike VgrG2a, VgrG2b belongs to a subclass of VgrG proteins, called evolved VgrGs that have an additional C-terminal extension with a putative zinc-dependent metallopeptidase domain. VrgG2b acts directly as an effector and promotes internalization by interacting with the host gamma-tubulin ring complex [
]. It also elicits toxicity also in the bacterial periplasm and disrupts bacterial cell morphology. This toxicity is counteracted by a cognate immunity protein []. In addition, it allows the delivery of the Tle3 antibacterial toxin to target cells where it exerts its toxicity [].This entry represents DUF2345, which is found in VgrG2a/b from Pseudomonas aeruginosa. This domain, present in both proteins, folds as a β-prism [
,
].
A number of eukaryotic proteins, which probably are sequence specific DNA-binding proteins that act as transcription factors, share a conserved domain of 40 to 50 amino acid residues. It has been proposed [
] that this domain is formed of two amphipathic helices joined by a variable length linker region that could form a loop. This 'helix-loop-helix' (HLH) domain mediates protein dimerization and has been found in the proteins listed below []. Most of these proteins have an extra basic region of about 15 amino acid residues that is adjacent to the HLH domain and specifically binds to DNA. They are referred as basic helix-loop-helix proteins (bHLH), and are classified in two groups: class A (ubiquitous) and class B (tissue-specific). Members of the bHLH family bind variations on the core sequence 'CANNTG', also referred to asthe E-box motif. The homo- or heterodimerization mediated by the HLH domain is independent of, but necessary for DNA binding, as two basic regions are required for DNA binding activity. The HLH proteins lacking the basic domain (Emc, Id) function as negative regulators, since they form heterodimers, but fail to bind DNA. The hairy-related proteins (hairy, E(spl), deadpan) also repress transcription although they can bind DNA. The proteins of this subfamily act together with co-repressor proteins, like groucho, through their -terminal motif WRPW.Proteins containing a HLH domain include:
The myc family of cellular oncogenes [
], which is currently known to contain four members: c-myc, N-myc, L-myc, and B-myc. The myc genes are thought to play a role in cellular differentiation and proliferation.Proteins involved in myogenesis (the induction of muscle cells). In mammals MyoD1 (Myf-3), myogenin (Myf-4), Myf-5, and Myf-6 (Mrf4 or herculin), in birds CMD1 (QMF-1), in Xenopus MyoD and MF25, in Caenorhabditis elegans CeMyoD, and in Drosophila nautilus (nau).Vertebrate proteins that bind specific DNA sequences ('E boxes') in various immunoglobulin chains enhancers: E2A or ITF-1 (E12/pan-2 and E47/pan-1), ITF-2 (tcf4), TFE3, and TFEB.Vertebrate neurogenic differentiation factor 1 that acts as differentiation factor during neurogenesis.Vertebrate MAX protein, a transcription regulator that forms a sequence- specific DNA-binding protein complex with myc or mad.Vertebrate Max Interacting Protein 1 (MXI1 protein) which acts as a transcriptional repressor and may antagonize myc transcriptional activity by competing for max.Proteins of the bHLH/PAS superfamily which are transcriptional activators. In mammals, AH receptor nuclear translocator (ARNT), single-minded homologues (SIM1 and SIM2), hypoxia-inducible factor 1 alpha (HIF1A), AH receptor (AHR), neuronal pas domain proteins (NPAS1 and NPAS2), endothelial pas domain protein 1 (EPAS1), mouse ARNT2, and human BMAL1. In Drosophila, single-minded (SIM), AH receptor nuclear translocator (ARNT), trachealess protein (TRH), and similar protein (SIMA).Mammalian transcription factors HES, which repress transcription by acting on two types of DNA sequences, the E box and the N box.Mammalian MAD protein (max dimerizer) which acts as transcriptional repressor and may antagonize myc transcriptional activity by competing for max.Mammalian Upstream Stimulatory Factor 1 and 2 (USF1 and USF2), which bind to a symmetrical DNA sequence that is found in a variety of viral and cellular promoters.Human lyl-1 protein; which is involved, by chromosomal translocation, in T- cell leukemia.Human transcription factor AP-4.Mouse helix-loop-helix proteins MATH-1 and MATH-2 which activate E box- dependent transcription in collaboration with E47.Mammalian stem cell protein (SCL) (also known as tal1), a protein which may play an important role in hemopoietic differentiation. SCL is involved, by chromosomal translocation, in stem-cell leukemia.Mammalian proteins Id1 to Id4 [
]. Id (inhibitor of DNA binding) proteins lack a basic DNA-binding domain but are able to form heterodimers with other HLH proteins, thereby inhibiting binding to DNA.Drosophila extra-macrochaetae (emc) protein, which participates in sensory organ patterning by antagonizing the neurogenic activity of the achaete- scute complex. Emc is the homologue of mammalian Id proteins.Human Sterol Regulatory Element Binding Protein 1 (SREBP-1), a transcriptional activator that binds to the sterol regulatory element 1 (SRE-1) found in the flanking region of the LDLR gene and in other genes.Drosophila achaete-scute (AS-C) complex proteins T3 (l'sc), T4 (scute), T5 (achaete) and T8 (asense). The AS-C proteins are involved in the determination of the neuronal precursors in the peripheral nervous system and the central nervous system.Mammalian homologues of achaete-scute proteins, the MASH-1 and MASH-2 proteins.Drosophila atonal protein (ato) which is involved in neurogenesis.
This entry represents LIM-type zinc finger (Znf) domains. LIM domains coordinate one or more zinc atoms, and are named after the three proteins (LIN-11, Isl1 and MEC-3) in which they were first found. They consist of two zinc-binding motifs that resemble GATA-like Znf's, however the residues holding the zinc atom(s) are variable, involving Cys, His, Asp or Glu residues. LIM domains are involved in proteins with differing functions, including gene expression, and cytoskeleton organisation and development [
,
]. Protein containing LIM Znf domains include:Caenorhabditis elegans mec-3; a protein required for the differentiation of the set of six touch receptor neurons in this nematode.C. elegans. lin-11; a protein required for the asymmetric division of vulval blast cells.Vertebrate insulin gene enhancer binding protein isl-1. Isl-1 binds to one of the two cis-acting protein-binding domains of the insulin gene.Vertebrate homeobox proteins lim-1, lim-2 (lim-5) and lim3.Vertebrate lmx-1, which acts as a transcriptional activator by binding to the FLAT element; a beta-cell-specific transcriptional enhancer found in the insulin gene.Mammalian LH-2, a transcriptional regulatory protein involved in the control of cell differentiation in developing lymphoid and neural cell types.Drosophila melanogaster (Fruit fly) protein apterous, required for the normal development of the wing and halter imaginal discs.Vertebrate protein kinases LIMK-1 and LIMK-2.Mammalian rhombotins. Rhombotin 1 (RBTN1 or TTG-1) and rhombotin-2 (RBTN2 or TTG-2) are proteins of about 160 amino acids whose genes are disrupted by chromosomal translocations in T-cell leukemia.Mammalian and avian cysteine-rich protein (CRP), a 192 amino-acid protein of unknown function. Seems to interact with zyxin.Mammalian cysteine-rich intestinal protein (CRIP), a small protein which seems to have a role in zinc absorption and may function as an intracellular zinc transport protein.Vertebrate paxillin, a cytoskeletal focal adhesion protein.Mus musculus (Mouse) testin which should not be confused with rat testin which is a thiol protease homologue (see
).
Helianthus annuus (Common sunflower) pollen specific protein SF3.Chicken zyxin. Zyxin is a low-abundance adhesion plaque protein which has been shown to interact with CRP.Yeast protein LRG1 which is involved in sporulation [
].Saccharomyces cerevisiae (Baker's yeast) rho-type GTPase activating protein RGA1/DBM1.C. elegans homeobox protein ceh-14.C. elegans homeobox protein unc-97.S. cerevisiae hypothetical protein YKR090w.C. elegans hypothetical proteins C28H8.6.These proteins generally contain two tandem copies of the LIM domain in their N-terminal section. Zyxin and paxillin are exceptions in that they contain respectively three and four LIM domains at their C-terminal extremity. In apterous, isl-1, LH-2, lin-11, lim-1 to lim-3, lmx-1 and ceh-14 and mec-3 there is a homeobox domain some 50 to 95 amino acids after the LIM domains.LIM domains contain seven conserved cysteine residues and a histidine. The arrangement followed by these conserved residues is:C-x(2)-C-x(16,23)-H-x(2)-[CH]-x(2)-C-x(2)-C-x(16,21)-C-x(2,3)-[CHD]LIM domains bind two zinc ions [
]. LIM does not bind DNA, rather it seems to act as an interface for protein-protein interaction.
The immunoglobulin (Ig) like fold, which consists of a β-sandwich of seven or more strands in two sheets with a greek-key topology, is one of the most common protein modules found in animals. Many different unrelated proteins share an Ig-like fold, which is often involved in interactions, commonly with other Ig-like domains via their β-sheets [
]. Of these, the "early"set (E set) domains are possibly related to the immunoglobulin (
) and/or fibronectin type III (
) Ig-like protein superfamilies. Ig-like E set domains include:
C-terminal domain of certain transcription factors, such as the pro-inflammatory transcription factor NF-kappaB, and the T-cell transcription factors NFAT1 and NFAT5 [
].Ig-like domains of sugar-utilising enzymes, such as galactose oxidase (C-terminal domain), sialidase (linker domain), and maltogenic amylase (N-terminal domain).C-terminal domain of arthropod haemocyanin, where many loops are inserted into the fold. These proteins act as dioxygen-transporting proteins.C-terminal domain of class II viral fusion proteins. These envelope glycoproteins are responsible for membrane fusion with target cells during viral invasion.Cytomegaloviral US (unique short) proteins. These type I membrane proteins help suppress the host immune response by modulating surface expression of MHC class I molecules [
].Molybdenium-containing oxidoreductase-like dimerisation domain found in enzymes such as sulphite reductase.ML domains found in cholesterol-binding epididymal secretory protein E1, and in a major house-dust mite allergen; ML domains are implicated in lipid recognition, particularly the recognition of pathogen-related products.Rho-GDI-like signalling proteins, which regulate the activity of small G proteins [
].Cytoplasmic domain of inward rectifier potassium channels such as Girk1 and Kirbac1.1. These channels act as regulators of excitability in eukaryotic cells.N-terminal domain of transglutaminases, including coagulation factor XIII; many loops are inserted into the fold in these proteins. These proteins act to catalyse the cross-linking of various protein substrates [
].Filamin repeat rod domain found in proteins such as the F-actin cross-linking gelation factor ABP-120. These proteins interact with a variety of cellular proteins, acting as signalling scaffolds [
].Arrestin family of proteins, which contain a tandem repeat of two elaborated Ig-like domains contacting each other head-to-head. These proteins are key to the redirection of GPCR signals to alternative pathways [
].C-terminal domain of arginine-specific cysteine proteases, such as Gingipain-R, which act as major virulence factors of Porphyromonas gingivalis (Bacteroides gingivalis).Copper-resistance proteins, such as CopC, which act as copper-trafficking proteins [
].Cellulosomal scaffoldin proteins, such as CipC module x2.1. These proteins act as scaffolding proteins of cellulosomes, which contain cellulose-degrading enzymes [
].Quinohaemoprotein amine dehydrogenases (A chain), which contain a tandem repeat of two Ig-like domains. These proteins function in electron transfer reactions.Internalin Ig-like domains, which are truncated and fused to a leucine-rich repeat domain. These proteins are required for host cell invasion of Listeria species.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].This entry represents the tyrosine protein kinase active site. It also matches a number of proteins belonging to the atypical serine/threonine protein kinase BUD32 family, which lack the conventional structural elements necessary for the substrate recognition and also lack the lysine residue that in all other serine/threonine kinases participates in the catalytic event.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].This group represents a tyrosine-protein kinase, Ret receptor type.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].This entry represents the receptor tyrosine kinases for HGF (hepatocyte growth factor) and MSP (macrophage-stimulating protein) [
]. The HGF receptor functions in cell proliferation, scattering, morphogenesis and survival [,
].
Tyrosine-protein kinase, receptor class II, conserved site
Type:
Conserved_site
Description:
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].A number of growth factors stimulate mitogenesis by interacting with a family
of cell surface receptors which possess an intrinsic, ligand-sensitive,protein tyrosine kinase activity [
]. These receptor tyrosine kinases (RTK)all share the same topology: an extracellular ligand-binding domain, a single
transmembrane region and a cytoplasmic kinase domain. However they can beclassified into at least five groups. The prototype for class II RTK's is the
insulin receptor, a heterotetramer of two alpha and two beta chains linked bydisulphide bonds. The alpha and beta chains are cleavage products of a
precursor molecule. The alpha chain contains the ligand binding site, the betachain transverses the membrane and contains the tyrosine protein kinase
domain.While only the insulin and the insulin growth factor I receptors are known to
exist in the tetrameric conformation specific to class II RTK's, all the aboveproteins share extensive homologies in their kinase domain, especially around
the putative site of autophosphorylation.
Pleckstrin homology (PH) domains are small modular domains that occur in a large variety of proteins and they have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner, enabling them to interact with other components of signal transduction pathways. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. The domains can bind phosphatidylinositol within biological membranes and proteins such as the beta/gamma subunits of heterotrimeric G proteins [] and protein kinase C []. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to phosphoinositide phosphates (PIPs) with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminal of the domain, which are not conserved across all PH domains [,
,
].PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.The 3D structure of several PH domains has been determined [
]. All known cases have a common structure consisting of two perpendicular anti-parallel β-sheets, followed by a C-terminal amphipathic helix. The loops connecting the β-strands differ greatly in length, making the PH domain relatively difficult to detect. There are no totally invariant residues within the PH domain.Proteins reported to contain one more PH domains belong to the following families:Pleckstrin, the protein where this domain was first detected, is the major substrate of protein kinase C in platelets. Pleckstrin is one of the rare proteins to contains two PH domains.Ser/Thr protein kinases such as the Akt/Rac family, the beta-adrenergic receptor kinases, the mu isoform of PKC and the trypanosomal NrkA family.Tyrosine protein kinases belonging to the Btk/Itk/Tec subfamily.Insulin Receptor Substrate 1 (IRS-1).Regulators of small G-proteins like guanine nucleotide releasing factor GNRP (Ras-GRF) (which contains 2 PH domains), guanine nucleotide exchange proteins like vav, dbl, SoS and Saccharomyces cerevisiae CDC24, GTPase activating proteins like rasGAP and BEM2/IPL2, and the human break point cluster protein bcr.Cytoskeletal proteins such as dynamin (see
), Caenorhabditis elegans kinesin-like protein unc-104 (see
), spectrin beta-chain, syntrophin (2 PH domains) and S. cerevisiae nuclear migration protein NUM1.
Mammalian phosphatidylinositol-specific phospholipase C (PI-PLC) (see
) isoforms gamma and delta. Isoform gamma contains two PH domains, the second one is split into two parts separated by about 400 residues.
Oxysterol binding proteins OSBP, S. cerevisiae OSH1 and YHR073w.Mouse protein citron, a putative rho/rac effector that binds to the GTP-bound forms of rho and rac.Several S. cerevisiae proteins involved in cell cycle regulation and bud formation like BEM2, BEM3, BUD4 and the BEM1-binding proteins BOI2 (BEB1) and BOI1 (BOB1).C. elegans protein MIG-10.C. elegans hypothetical proteins C04D8.1, K06H7.4 and ZK632.12.S. cerevisiae hypothetical proteins YBR129c and YHR155w.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].
This entry represents a conserved sequence region found in the N-terminal domain of several lipid-binding serum glycoproteins. The N- and C-terminal domains of these proteins share a similar two-layer alpha/beta structure, but they show little sequence identity. Proteins containing this N-terminal domain include:Bactericidal permeability-increasing protein (BPI)Lipopolysaccharide-binding protein (LBP)Cholesteryl ester transfer protein (CETP)Phospholipid transfer protein (PLTP)Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC)Bactericidal permeability-increasing protein (BPI) is a potent antimicrobial protein of 456 residues that binds to and neutralises lipopolysaccharides from the outer membrane of Gram-negative bacteria [
]. BPI contains two domains that adopt the same structural fold, even though they have little sequence similarity []. Lipopolysaccharide-binding protein (LBP) is an endotoxin-binding protein that is closely related to BPI, and functions with it to facilitate an integrated host response to invading Gram-negative bacteria [
].Cholesteryl ester transfer protein (CETP) is a glycoprotein that facilitates the transfer of lipids (cholesteryl esters and triglycerides) between the different lipoproteins that transport them through plasma, including HDL, LDL, VLDL and chylomicrons. These lipoproteins shield the lipids from water by encapsulating them within a coating of polar lipids and proteins [
].Phospholipid transfer protein (PLTP) exchanges phospholipids between lipoproteins and remodels high-density lipoproteins (HDLs) [
].Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC) is a potential host defensive protein that is secreted from the submucosal gland to the saliva and nasal lavage fluid. PLUNC aapears to be a secreted product of neutrophil granules that participates in an aspect of the inflammatory response that contributes to host defence [
]. Short palate, lung and nasal epithelium clone 1 (SPLUNC1) may bind the lipopolysaccharide of Gram-negative nanobacteria, thereby playing an important role in the host defence of nasopharyngeal epithelium [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].This group represents a membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].This entry represents Fes/Fps family of non-receptor tyrosine kinases.
Tyrosine-protein kinase, receptor class V, conserved site
Type:
Conserved_site
Description:
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [
]:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].A number of growth factors stimulate mitogenesis by interacting with a family
of cell surface receptors which possess an intrinsic, ligand-sensitive,protein tyrosine kinase activity [
]. These receptor tyrosine kinases (RTK)all share the same topology: an extracellular ligand-binding domain, a single
transmembrane region and a cytoplasmic kinase domain and have beenclassified into at least five groups on the basis of sequence similarities.
The extracellular domain of class V RTK's has 16 conserved cysteine residues that are probably involved in
disulphide bonds; this region is followed by two copies of a fibronectin typeIII domain. The ligands for these receptors are proteins known as ephrins. The EPHA subtype receptors bind to GPI-anchored ephrins while the EPHB subtype
receptors bind to type-I membrane ephrins.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].Angiogenesis is a physiological process whereby new blood vessels are formed from existing ones. It is essential for tissue repair and regeneration during wound healing but also plays important roles in many pathological processes including tumor growth and metastasis [
,
]. Angiogenesis is regulated in part by the receptor protein tyrosine kinase Tie2 and its ligands, the angiopoietins. The angiopoietin-binding site is harbord by the N-terminal two immunoglobulin-like (Ig-like) domains of Tie2 [].The angiopoietin-1 receptor contains the Tie-2 Ig-like domain. This protein is a tyrosine-kinase transmembrane receptor for angiopoietin 1. It probably regulates endothelial cell proliferation, differentiation and guides the proper patterning of endothelial cells during blood vessel formation.Tie2 contains not two but three immunoglobulin domains. They fold together with the three epidermal growth factor domains to form a compact, arrowhead-shaped structure [
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].Janus kinases (JAKs) are tyrosine kinases that function in membrane-proximal signalling events initiated by a variety of extracellular factors binding to cell surface receptors [
]. Many type I and II cytokine receptors lack a protein tyrosine kinase domain and rely on JAKs to initiate the cytoplasmic signal transduction cascade. Ligand binding induces oligomerisation of the receptors, which then activates the cytoplasmic receptor-associated JAKs. These subsequently phosphorylate tyrosine residues along the receptor chains with which they are associated. The phosphotyrosine residues are a target for a variety of SH2 domain-containing transducer proteins. Amongst these are the signal transducers and activators of transcription (STAT) proteins, which, after binding to the receptor chains, are phosphorylated by the JAK proteins. Phosphorylation enables the STAT proteins to dimerise and translocate into the nucleus, where they alter the expression of cytokine-regulated genes. This system is known as the JAK-STAT pathway.
Four mammalian JAK family members have been identified: JAK1, JAK2, JAK3, and TYK2. They are relatively large kinases of approximately 1150 amino acids, with molecular weights of ~120-130kDa. Their amino acid sequences are characterised by the presence of 7 highly conserved domains, termed JAK homology (JH) domains. The C-terminal domain (JH1) is responsible for the tyrosine kinase function. The next domain in the sequence (JH2) is known as the tyrosine kinase-like domain, as its sequence shows high similarity to functional kinases but does not possess any catalytic activity. Although the function of this domain is not well established, there is some evidence for a regulatory role on the JH1 domain, thus modulating catalytic activity. The N-terminal portion of the JAKs (spanning JH7 to JH3) is important for receptor association and non-catalytic activity, and consists of JH3-JH4, which is homologous to the SH2 domain, and lastly JH5-JH7, which is a FERM domain.This represents the non-receptor tyrosine kinase JAK3, which is involved in the interleukin-2 and interleukin-4 signalling pathway. Jak3 phosphorylates STAT6, IRS1, IRS2 and PI3K [
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents RIO kinase, they exhibit little sequence similarity with eukaryotic protein kinases, and are classified as atypical protein kinases [
]. The conformation of ATP when bound to the RIO kinases is unique when compared with ePKs, such as serine/threonine kinases or the insulin receptor tyrosine kinase, suggesting that the detailed mechanism by which the catalytic aspartate of RIO kinases participates in phosphoryl transfer may not be identical to that employed in known serine/threonine ePKs. Representatives of the RIO family are present in organisms varying from Archaea to humans, although the RIO3 proteins have only been identified in multicellular eukaryotes, to date. Yeast Rio1 and Rio2 proteins are required for proper cell cycle progression and chromosome maintenance, and are necessary for survival of the cells. These proteins are involved in the processing of 20 S pre-rRNA via late 18 S rRNA processing.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents RIO kinase, they exhibit little sequence similarity with eukaryotic protein kinases, and are classified as atypical protein kinases [
]. The conformation of ATP when bound to the RIO kinases is unique when compared with ePKs, such as serine/threonine kinases or the insulin receptor tyrosine kinase, suggesting that the detailed mechanism by which the catalytic aspartate of RIO kinases participates in phosphoryl transfer may not be identical to that employed in known serine/threonine ePKs. Representatives of the RIO family are present in organisms varying from Archaea to humans, although the RIO3 proteins have only been identified in multicellular eukaryotes, to date. Yeast Rio1 and Rio2 proteins are required for proper cell cycle progression and chromosome maintenance, and are necessary for survival of the cells. These proteins are involved in the processing of 20 S pre-rRNA via late 18 S rRNA processing.
This entry represents a structural domain with a multi-helical fold consisting of a 4-helical bundle with a left-handed twist and an up-and-down topology. This domain can be divided into two all-α subdomains. This domain is found in regulation of G-protein signalling (RGS) proteins, as well as other related proteins, including:RGS4 [
].RGS9 [
].G-alpha interacting protein GaIP [
].Axin [
].p115RhoGEF [
].Pdz-RhoGEF [
].G-protein coupled receptor kinase 2 N-terminal domain [
].RGS (Regulator of G Protein Signalling) proteins are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways. Upon activation by GPCRs, heterotrimeric G proteins exchange GDP for GTP, are released from the receptor, and dissociate into free, active GTP-bound alpha subunit and beta-gamma dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the alpha subunit (
), which can then bind the beta-gamma dimer (
,
) and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound alpha subunits by stabilising the G protein transition state.
All RGS proteins contain an 'RGS-box' (or RGS domain), which is required for activity. Some small RGS proteins such as RGS1 and RGS4 are comprised of little more than an RGS domain, while others also contain additional domains that confer further functionality. RGS domains can be found in conjunction with a variety of domains, including: DEP for membrane targeting (
), PDZ for binding to GPCRs (
), PTB for phosphotyrosine-binding (
), RBD for Ras-binding (
), GoLoco for guanine nucleotide inhibitor activity (
), PX for phosphatidylinositol-binding (
), PXA that is associated with PX (
), PH for stimulating guanine nucleotide exchange (
), and GGL (G protein gamma subunit-like) for binding G protein beta subunits (
). Those RGS proteins that contain GGL domains can interact with G protein beta subunits to form novel dimers that prevent G protein gamma subunit binding and G protein alpha subunit association, thereby preventing heterotrimer formation.
This entry represents a structural domain superfamily with a multi-helical fold consisting of a 4-helical bundle with a left-handed twist and an up-and-down topology. This domain can be divided into two all-alpha subdomains. This domain is found in regulation of G-protein signalling (RGS) proteins, as well as other related proteins, including:RGS4 [
].RGS9 [
].G-alpha interacting protein GaIP [
].Axin [
].p115RhoGEF [
].Pdz-RhoGEF [
].G-protein coupled receptor kinase 2 N-terminal domain [
].RGS (Regulator of G Protein Signalling) proteins are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways. Upon activation by GPCRs, heterotrimeric G proteins exchange GDP for GTP, are released from the receptor, and dissociate into free, active GTP-bound alpha subunit and beta-gamma dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the alpha subunit (
), which can then bind the beta-gamma dimer (
,
) and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound alpha subunits by stabilising the G protein transition state.
All RGS proteins contain an 'RGS-box' (or RGS domain), which is required for activity. Some small RGS proteins such as RGS1 and RGS4 are comprised of little more than an RGS domain, while others also contain additional domains that confer further functionality. RGS domains can be found in conjunction with a variety of domains, including: DEP for membrane targeting (
), PDZ for binding to GPCRs (
), PTB for phosphotyrosine-binding (
), RBD for Ras-binding (
), GoLoco for guanine nucleotide inhibitor activity (
), PX for phosphatidylinositol-binding (
), PXA that is associated with PX (
), PH for stimulating guanine nucleotide exchange (
), and GGL (G protein gamma subunit-like) for binding G protein beta subunits (
). Those RGS proteins that contain GGL domains can interact with G protein beta subunits to form novel dimers that prevent G protein gamma subunit binding and G protein alpha subunit association, thereby preventing heterotrimer formation.
Tyrosine-protein kinase ephrin type A/B receptor-like
Type:
Domain
Description:
This entry represents a domain found in various ephrin type A and B receptors, which have tyrosine kinase activity.Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].Janus kinases (JAKs) are tyrosine kinases that function in membrane-proximal signalling events initiated by a variety of extracellular factors binding to cell surface receptors [
]. Many type I and II cytokine receptors lack a protein tyrosine kinase domain and rely on JAKs to initiate the cytoplasmic signal transduction cascade. Ligand binding induces oligomerisation of the receptors, which then activates the cytoplasmic receptor-associated JAKs. These subsequently phosphorylate tyrosine residues along the receptor chains with which they are associated. The phosphotyrosine residues are a target for a variety of SH2 domain-containing transducer proteins. Amongst these are the signal transducers and activators of transcription (STAT) proteins, which, after binding to the receptor chains, are phosphorylated by the JAK proteins. Phosphorylation enables the STAT proteins to dimerise and translocate into the nucleus, where they alter the expression of cytokine-regulated genes. This system is known as the JAK-STAT pathway.Four mammalian JAK family members have been identified: JAK1, JAK2, JAK3, and TYK2. They are relatively large kinases of approximately 1150 amino acids, with molecular weights of ~120-130kDa. Their amino acid sequences are characterised by the presence of 7 highly conserved domains, termed JAK homology (JH) domains. The C-terminal domain (JH1) is responsible for the tyrosine kinase function. The next domain in the sequence (JH2) is known as the tyrosine kinase-like domain, as its sequence shows high similarity to functional kinases but does not possess any catalytic activity. Although the function of this domain is not well established, there is some evidence for a regulatory role on the JH1 domain, thus modulating catalytic activity. The N-terminal portion of the JAKs (spanning JH7 to JH3) is important for receptor association and non-catalytic activity, and consists of JH3-JH4, which is homologous to the SH2 domain, and lastly JH5-JH7, which is a FERM domain.This entry represents the non-receptor tyrosine kinases Jak and Tyk2:Jak1 appears to be required in early development for specific cell migrations (epiboly), for the expression of the homeobox protein goosecoid and for the formation of anterior structures [].Jak2 plays a role in leptin signalling and in the control of body weight. It is involved in interleukin-3, and probably interleukin-23, signal transduction [
].Jak3 is involved in the interleukin-2 and interleukin-4 signalling pathway. It phosphorylates STAT6, IRS1, IRS2 and PI3K [
].Tyk2 is probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signalling. It phosphorylates the interferon-alpha/beta receptor alpha chain [
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].Janus kinases (JAKs) are tyrosine kinases that function in membrane-proximal signalling events initiated by a variety of extracellular factors binding to cell surface receptors [
]. Many type I and II cytokine receptors lack a protein tyrosine kinase domain and rely on JAKs to initiate the cytoplasmic signal transduction cascade. Ligand binding induces oligomerisation of the receptors, which then activates the cytoplasmic receptor-associated JAKs. These subsequently phosphorylate tyrosine residues along the receptor chains with which they are associated. The phosphotyrosine residues are a target for a variety of SH2 domain-containing transducer proteins. Amongst these are the signal transducers and activators of transcription (STAT) proteins, which, after binding to the receptor chains, are phosphorylated by the JAK proteins. Phosphorylation enables the STAT proteins to dimerise and translocate into the nucleus, where they alter the expression of cytokine-regulated genes. This system is known as the JAK-STAT pathway.Four mammalian JAK family members have been identified: JAK1, JAK2, JAK3, and TYK2. They are relatively large kinases of approximately 1150 amino acids, with molecular weights of ~120-130kDa. Their amino acid sequences are characterised by the presence of 7 highly conserved domains, termed JAK homology (JH) domains. The C-terminal domain (JH1) is responsible for the tyrosine kinase function. The next domain in the sequence (JH2) is known as the tyrosine kinase-like domain, as its sequence shows high similarity to functional kinases but does not possess any catalytic activity. Although the function of this domain is not well established, there is some evidence for a regulatory role on the JH1 domain, thus modulating catalytic activity. The N-terminal portion of the JAKs (spanning JH7 to JH3) is important for receptor association and non-catalytic activity, and consists of JH3-JH4, which is homologous to the SH2 domain, and lastly JH5-JH7, which is a FERM domain.This represents the non-receptor tyrosine kinase JAK1, which is involved in the IFN-alpha/beta/gamma signal pathway. Jak1 acts as the kinase partner for the interleukin (IL)-2 receptor [
] and interleukin (IL)-10 receptor []. It directly phosphorylates STAT but also activates STAT signalling through the transactivation of other JAK kinases associated with signalling receptors [,
].JAK1 was initially cloned using a PCR-based strategy utilising degenerate
primers corresponding to conserved motifs within the catalytic domain of protein-tyrosine kinases [
]. In common with JAK2 and TYK2, and by contrastwith JAK3, JAK1 appears to be ubiquitously expressed.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [
]:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].This entry represents the insulin receptor, as well as related insulin-like receptors. The insulin receptor binds insulin and has a tyrosine-protein kinase activity, and mediates the metabolic functions of insulin. Binding to insulin stimulates the association of the receptor with downstream mediators, including IRS1 and phosphatidylinositol 3'-kinase (PI3K). The insulin receptor can activate PI3K either directly by binding to the p85 regulatory subunit, or indirectly via IRS1. When the insulin receptor is present in a hybrid receptor with IGF1R (insulin growth factor receptor), it binds IGF1 (insulin growth factor 1) [
,
,
].
This entry represents the N-terminal domain found in several lipid-binding serum glycoproteins. The N- and C-terminal domains share a similar two-layer alpha/beta structure, but they show little sequence identity. Proteins containing this N-terminal domain include:Bactericidal permeability-increasing protein (BPI)Lipopolysaccharide-binding protein (LBP)Cholesteryl ester transfer protein (CETP)Phospholipid transfer protein (PLTP)Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC)Bactericidal permeability-increasing protein (BPI) is a potent antimicrobial protein of 456 residues that binds to and neutralises lipopolysaccharides from the outer membrane of Gram-negative bacteria [
]. BPI contains two domains that adopt the same structural fold, even though they have little sequence similarity []. Lipopolysaccharide-binding protein (LBP) is an endotoxin-binding protein that is closely related to, and functions in a co-ordinated manner with BPI to facilitate an integrated host response to invading Gram-negative bacteria [
].Cholesteryl ester transfer protein (CETP) is a glycoprotein that facilitates the transfer of lipids (cholesteryl esters and triglycerides) between the different lipoproteins that transport them through plasma, including HDL, LDL, VLDL and chylomicrons. These lipoproteins shield the lipids from water by encapsulating them within a coating of polar lipids and proteins [
].Phospholipid transfer protein (PLTP) exchanges phospholipids between lipoproteins and remodels high-density lipoproteins (HDLs) [
].Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC) is a potential host defensive protein that is secreted from the submucosal gland to the saliva and nasal lavage fluid. PLUNC appears to be a secreted product of neutrophil granules that participates in an aspect of the inflammatory response that contributes to host defence [
]. Short palate, lung and nasal epithelium clone 1 (SPLUNC1) may bind the lipopolysaccharide of Gram-negative nanobacteria, thereby playing an important role in the host defence of nasopharyngeal epithelium [].
This entry represents the C-terminal domain found in several lipid-binding serum glycoproteins. The N- and C-terminal domains share a similar two-layer alpha/beta structure, but they show little sequence identity. Proteins containing this C-terminal domain include:Bactericidal permeability-increasing protein (BPI)Lipopolysaccharide-binding protein (LBP)Cholesteryl ester transfer protein (CETP)Phospholipid transfer protein (PLTP)Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC)Bactericidal permeability-increasing protein (BPI) is a potent antimicrobial protein of 456 residues that binds to and neutralises lipopolysaccharides from the outer membrane of Gram-negative bacteria [
]. BPI contains two domains that adopt the same structural fold, even though they have little sequence similarity []. Lipopolysaccharide-binding protein (LBP) is an endotoxin-binding protein that is closely related to, and functions in a co-ordinated manner with BPI to facilitate an integrated host response to invading Gram-negative bacteria [
].Cholesteryl ester transfer protein (CETP) is a glycoprotein that facilitates the transfer of lipids (cholesteryl esters and triglycerides) between the different lipoproteins that transport them through plasma, including HDL, LDL, VLDL and chylomicrons. These lipoproteins shield the lipids from water by encapsulating them within a coating of polar lipids and proteins [
].Phospholipid transfer protein (PLTP) exchanges phospholipids between lipoproteins and remodels high-density lipoproteins (HDLs) [
].Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC) is a potential host defensive protein that is secreted from the submucosal gland to the saliva and nasal lavage fluid. PLUNC aapears to be a secreted product of neutrophil granules that participates in an aspect of the inflammatory response that contributes to host defence [
]. Short palate, lung and nasal epithelium clone 1 (SPLUNC1) may bind the lipopolysaccharide of Gram-negative nanobacteria, thereby playing an important role in the host defence of nasopharyngeal epithelium [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Eukaryotic protein kinases [
,
,
,
] are enzymesthat belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. In the N-terminal extremity of the catalytic domain there is a
glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. In the central part of the catalytic domain there is a conserved aspartic acid residue, which is important for the catalytic activity of the enzyme []. This signature contains the active site aspartate residue.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Casein kinase, a ubiquitous, well-conserved protein kinase involved in cell metabolism and differentiation, is characterised by its preference for Ser or Thr in acidic stretches of amino acids. The enzyme is a tetramer of 2 alpha- and 2 beta-subunits [
,
]. However, some species (e.g., mammals) possess 2 related forms of the alpha-subunit (alpha and alpha'), while others (e.g., fungi) possess 2 related beta-subunits (beta and beta') []. The alpha-subunit is the catalytic unit and contains regions characteristic of serine/threonine protein kinases. The beta-subunit is believed to be regulatory, possessing an N-terminal auto-phosphorylation site, an internal acidic domain, and a potential metal-binding motif []. The beta subunit is a highly conserved protein of about 25kDa that contains, in its central section, a cysteine-rich motif, CX(n)C, that could be involved in binding a metal such as zinc []. The mammalian beta-subunit gene promoter shares common features with those of other mammalian protein kinases and is closely related to the promoter of the regulatory subunit of cAMP-dependent protein kinase [].This superfamily represents the N-terminal α-helical domain, which has an orthogonal bundle topology.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].SYK is a positive effector of B-cell antigen receptor (BCR) stimulated responses [
,
]. ZAP-70 plays a role in T-cell development and lymphocyte activation. It is essential for TCR-mediated IL-2 production [,
].The N-terminal region of ZAP-70 consists of two SH2 domains that are connected by an helical region. The overall fold is Y shaped, with the intervening residues forming the stem [
]. This superfamily represents the inter-SH2 domain found in ZAP-70 and SYK kinases.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].TYK2 was first identified by low-stringency hybridisation screening of a
human lymphoid cDNA library with the catalytic domain of proto-oncogene c-fms [
]. Mouse and puffer fish orthlogues have also been identified. In common with JAK1 and JAK2, and by contrast with JAK3, TYK2 appears to be
ubiquitously expressed. This entry represents the N-terminal region of TYK2.
The FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane [
]. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton. The FERM domain is located at the N terminus of the majority of FERM-containing proteins [,
], which includes: Band 4.1, which links the spectrin-actin cytoskeleton of erythrocytes to the plasma membrane.Ezrin, a component of the undercoat of the microvilli plasma membrane.Moesin, which is probably involved in binding major cytoskeletal structures to the plasma membrane.Radixin, which is involved in the binding of the barbed end of actin filaments to the plasma membrane in the undercoat of the cell- to-cell adherens junction.Talin, a cytoskeletal protein concentrated in regions of cell-substratum contact and, in lymphocytes, of cell-cell contacts.Filopodin, a slime mold protein that binds actin and which is involved in the control of cell motility and chemotaxis.Merlin (or schwannomin).Protein NBL4.Unconventional myosins X, VIIa and XV, which are mutated in congenital deafness.Focal-adhesion kinases (FAKs), cytoplasmic protein tyrosine kinases involved in signalling through integrins.Janus tyrosine kinases (JAKs), cytoplasmic tyrosine kinases that are non-covalently associated with the cytoplasmic tails of receptors for cytokines or polypeptidic hormones.Non-receptor tyrosine-protein kinase TYK2.Protein-tyrosine phosphatases PTPN3 and PTPN4, enzyme that appear to act at junctions between the membrane and the cytoskeleton.Protein-tyrosine phosphatases PTPN14 and PTP-D1, PTP-RL10 and PTP2E.Caenorhabditis elegans protein phosphatase ptp-1.Ezrin, moesin, and radixin are highly related proteins (ERM protein family), but the other proteins in which the FERM domain is found do not share any region of similarity outside of this domain. ERM proteins are made of three domains, the FERM domain, a central helical domain and a C-terminal tail domain, which binds F-actin. The amino-acid sequence of the FERM domain is highly conserved among ERM proteins and is responsible for membrane association by direct binding to the cytoplasmic domain or tail of integral membrane proteins. ERM proteins are regulated by an intramolecular association of the FERM and C-terminal tail domains that masks their binding sites for other molecules. For cytoskeleton-membrane cross-linking, the dormant molecules becomes activated and the FERM domain attaches to the membrane by binding specific membrane proteins, while the last 34 residues of the tail bind actin filaments. Aside from binding to membranes, the activated FERM domain of ERM proteins can also bind the guanine nucleotide dissociation inhibitor of Rho GTPase (RhoDGI), which suggests that in addition to functioning as a cross-linker, ERM proteins may influence Rho signalling pathways. The crystal structure of the FERM domain reveals that it is composed of three structural modules (F1, F2, and F3) that together form a compact clover-shaped structure [
].The FERM domain has also been called the amino-terminal domain, the 30kDa domain, 4.1N30, the membrane-cytoskeletal-linking domain, the ERM-like domain, the ezrin-like domain of the band 4.1 superfamily, the conserved N-terminal region, and the membrane attachment domain [
].
The FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane [
]. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton. The FERM domain is located at the N terminus of the majority of FERM-containing proteins [,
], which includes: Band 4.1, which links the spectrin-actin cytoskeleton of erythrocytes to the plasma membrane.Ezrin, a component of the undercoat of the microvilli plasma membrane.Moesin, which is probably involved in binding major cytoskeletal structures to the plasma membrane.Radixin, which is involved in the binding of the barbed end of actin filaments to the plasma membrane in the undercoat of the cell- to-cell adherens junction.Talin, a cytoskeletal protein concentrated in regions of cell-substratum contact and, in lymphocytes, of cell-cell contacts.Filopodin, a slime mold protein that binds actin and which is involved in the control of cell motility and chemotaxis.Merlin (or schwannomin).Protein NBL4.Unconventional myosins X, VIIa and XV, which are mutated in congenital deafness.Focal-adhesion kinases (FAKs), cytoplasmic protein tyrosine kinases involved in signalling through integrins.Janus tyrosine kinases (JAKs), cytoplasmic tyrosine kinases that are non-covalently associated with the cytoplasmic tails of receptors for cytokines or polypeptidic hormones.Non-receptor tyrosine-protein kinase TYK2.Protein-tyrosine phosphatases PTPN3 and PTPN4, enzyme that appear to act at junctions between the membrane and the cytoskeleton.Protein-tyrosine phosphatases PTPN14 and PTP-D1, PTP-RL10 and PTP2E.Caenorhabditis elegans protein phosphatase ptp-1.Ezrin, moesin, and radixin are highly related proteins (ERM protein family), but the other proteins in which the FERM domain is found do not share any region of similarity outside of this domain. ERM proteins are made of three domains, the FERM domain, a central helical domain and a C-terminal tail domain, which binds F-actin. The amino-acid sequence of the FERM domain is highly conserved among ERM proteins and is responsible for membrane association by direct binding to the cytoplasmic domain or tail of integral membrane proteins. ERM proteins are regulated by an intramolecular association of the FERM and C-terminal tail domains that masks their binding sites for other molecules. For cytoskeleton-membrane cross-linking, the dormant molecules becomes activated and the FERM domain attaches to the membrane by binding specific membrane proteins, while the last 34 residues of the tail bind actin filaments. Aside from binding to membranes, the activated FERM domain of ERM proteins can also bind the guanine nucleotide dissociation inhibitor of Rho GTPase (RhoDGI), which suggests that in addition to functioning as a cross-linker, ERM proteins may influence Rho signalling pathways. The crystal structure of the FERM domain reveals that it is composed of three structural modules (F1, F2, and F3) that together form a compact clover-shaped structure [
].The FERM domain has also been called the amino-terminal domain, the 30kDa domain, 4.1N30, the membrane-cytoskeletal-linking domain, the ERM-like domain, the ezrin-like domain of the band 4.1 superfamily, the conserved N-terminal region, and the membrane attachment domain [
].
The FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane [
]. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton. The FERM domain is located at the N terminus of the majority of FERM-containing proteins [,
], which includes: Band 4.1, which links the spectrin-actin cytoskeleton of erythrocytes to the plasma membrane.Ezrin, a component of the undercoat of the microvilli plasma membrane.Moesin, which is probably involved in binding major cytoskeletal structures to the plasma membrane.Radixin, which is involved in the binding of the barbed end of actin filaments to the plasma membrane in the undercoat of the cell- to-cell adherens junction.Talin, a cytoskeletal protein concentrated in regions of cell-substratum contact and, in lymphocytes, of cell-cell contacts.Filopodin, a slime mold protein that binds actin and which is involved in the control of cell motility and chemotaxis.Merlin (or schwannomin).Protein NBL4.Unconventional myosins X, VIIa and XV, which are mutated in congenital deafness.Focal-adhesion kinases (FAKs), cytoplasmic protein tyrosine kinases involved in signalling through integrins.Janus tyrosine kinases (JAKs), cytoplasmic tyrosine kinases that are non-covalently associated with the cytoplasmic tails of receptors for cytokines or polypeptidic hormones.Non-receptor tyrosine-protein kinase TYK2.Protein-tyrosine phosphatases PTPN3 and PTPN4, enzyme that appear to act at junctions between the membrane and the cytoskeleton.Protein-tyrosine phosphatases PTPN14 and PTP-D1, PTP-RL10 and PTP2E.Caenorhabditis elegans protein phosphatase ptp-1.Ezrin, moesin, and radixin are highly related proteins (ERM protein family), but the other proteins in which the FERM domain is found do not share any region of similarity outside of this domain. ERM proteins are made of three domains, the FERM domain, a central helical domain and a C-terminal tail domain, which binds F-actin. The amino-acid sequence of the FERM domain is highly conserved among ERM proteins and is responsible for membrane association by direct binding to the cytoplasmic domain or tail of integral membrane proteins. ERM proteins are regulated by an intramolecular association of the FERM and C-terminal tail domains that masks their binding sites for other molecules. For cytoskeleton-membrane cross-linking, the dormant molecules becomes activated and the FERM domain attaches to the membrane by binding specific membrane proteins, while the last 34 residues of the tail bind actin filaments. Aside from binding to membranes, the activated FERM domain of ERM proteins can also bind the guanine nucleotide dissociation inhibitor of Rho GTPase (RhoDGI), which suggests that in addition to functioning as a cross-linker, ERM proteins may influence Rho signalling pathways. The crystal structure of the FERM domain reveals that it is composed of three structural modules (F1, F2, and F3) that together form a compact clover-shaped structure [
].The FERM domain has also been called the amino-terminal domain, the 30kDa domain, 4.1N30, the membrane-cytoskeletal-linking domain, the ERM-like domain, the ezrin-like domain of the band 4.1 superfamily, the conserved N-terminal region, and the membrane attachment domain [
].
Tyrosine-protein kinase, receptor class III, conserved site
Type:
Conserved_site
Description:
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].A number of growth factors stimulate mitogenesis by interacting with a family of cell surface receptors which possess an intrinsic, ligand-sensitive, protein tyrosine kinase activity [
]. These receptor tyrosine kinases (RTK) all share the same topology: an extracellular ligand-binding domain, a single transmembrane region and a cytoplasmic kinase domain. However they can be classified into at least five groups. The class III RTK's are characterised by the presence of five to seven immunoglobulin-like domains [] in their extracellular section. Their kinase domain differs from that of other RTK's by the insertion of a stretch of 70 to 100 hydrophilic residues in the middle of this domain. The receptors currently known to belong to class III are:Platelet-derived growth factor receptor (PDGF-R). PDGF-R exists as a homo- or heterodimer of two related chains: alpha and beta [
].Macrophage colony stimulating factor receptor (CSF-1-R) (also known as the fms oncogene).Stem cell factor (mast cell growth factor) receptor (also known as the kit oncogene).Vascular endothelial growth factor (VEGF) receptors Flt-1 and Flk-1/KDR [
].Fl cytokine receptor Flk-2/Flt-3 [
].The putative receptor Flt-4 [
].This entry represents a short, conserved region found within these proteins.
The FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane [
]. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton. The FERM domain is located at the N terminus of the majority of FERM-containing proteins [
,
], which includes: Band 4.1, which links the spectrin-actin cytoskeleton of erythrocytes to the plasma membrane.Ezrin, a component of the undercoat of the microvilli plasma membrane.Moesin, which is probably involved in binding major cytoskeletal structures to the plasma membrane.Radixin, which is involved in the binding of the barbed end of actin filaments to the plasma membrane in the undercoat of the cell- to-cell adherens junction.Talin, a cytoskeletal protein concentrated in regions of cell-substratum contact and, in lymphocytes, of cell-cell contacts.Filopodin, a slime mold protein that binds actin and which is involved in the control of cell motility and chemotaxis.Merlin (or schwannomin).Protein NBL4.Unconventional myosins X, VIIa and XV, which are mutated in congenital deafness.Focal-adhesion kinases (FAKs), cytoplasmic protein tyrosine kinases involved in signalling through integrins.Janus tyrosine kinases (JAKs), cytoplasmic tyrosine kinases that are non-covalently associated with the cytoplasmic tails of receptors for cytokines or polypeptidic hormones.Non-receptor tyrosine-protein kinase TYK2.Protein-tyrosine phosphatases PTPN3 and PTPN4, enzyme that appear to act at junctions between the membrane and the cytoskeleton.Protein-tyrosine phosphatases PTPN14 and PTP-D1, PTP-RL10 and PTP2E.Caenorhabditis elegans protein phosphatase ptp-1.Ezrin, moesin, and radixin are highly related proteins (ERM protein family), but the other proteins in which the FERM domain is found do not share any region of similarity outside of this domain. ERM proteins are made of three domains, the FERM domain, a central helical domain and a C-terminal tail domain, which binds F-actin. The amino-acid sequence of the FERM domain is highly conserved among ERM proteins and is responsible for membrane association by direct binding to the cytoplasmic domain or tail of integral membrane proteins. ERM proteins are regulated by an intramolecular association of the FERM and C-terminal tail domains that masks their binding sites for other molecules. For cytoskeleton-membrane cross-linking, the dormant molecules becomes activated and the FERM domain attaches to the membrane by binding specific membrane proteins, while the last 34 residues of the tail bind actin filaments. Aside from binding to membranes, the activated FERM domain of ERM proteins can also bind the guanine nucleotide dissociation inhibitor of Rho GTPase (RhoDGI), which suggests that in addition to functioning as a cross-linker, ERM proteins may influence Rho signalling pathways. The crystal structure of the FERM domain reveals that it is composed of three structural modules (F1, F2, and F3) that together form a compact clover-shaped structure [
].The FERM domain has also been called the amino-terminal domain, the 30kDa domain, 4.1N30, the membrane-cytoskeletal-linking domain, the ERM-like domain, the ezrin-like domain of the band 4.1 superfamily, the conserved N-terminal region, and the membrane attachment domain [
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents proteins predicted to be serine/threonine-protein kinases (
), such as YKL116C from Saccharomyces cerevisiae (Baker's yeast).
Diacylglycerol (DAG) is a second messenger that acts as a protein kinase C activator. The DAG kinase domain is assumed to be an accessory domain. Upon cell stimulation, DAG kinase converts DAG into phosphatidate, initiating the resynthesis of phosphatidylinositols and attenuating protein kinase C activity. It catalyses the reaction: ATP + 1,2-diacylglycerol = ADP +
1,2-diacylglycerol 3-phosphate. The enzyme is stimulated by calcium and phosphatidylserine and phosphorylated by protein kinase C. This domain is always associated with .
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].
This family consists of the protein translocase subunit SecY and protein transport protein Sec61 subunit alpha (Sec61a).Sec61a is part of the Sec61 complex, which plays a crucial role in the insertion of secretory and membrane polypeptides into the ER. It is required for assembly of membrane and secretory proteins. Secretion across the inner membrane in some Gram-negative bacteria occurs via the preprotein translocase pathway. Proteins are produced in the cytoplasm as precursors, and require a chaperone subunit to direct them to the translocase component [
]. From there, the mature proteins are either targeted to the outer membrane, or remain as periplasmic proteins. The translocase protein subunits are encoded on the bacterial chromosome.The translocase itself comprises 7 proteins, including a chaperone protein (SecB), an ATPase (SecA), an integral membrane complex (SecY, SecE and SecG), and two additional membrane proteins that promote the release of the mature peptide into the periplasm (SecD and SecF) [
]. The chaperone protein SecB [] is a highly acidic homotetrameric protein that exists as a "dimer of dimers"in the bacterial cytoplasm. SecB maintains preproteins in an unfolded state after translation, and targets these to the peripheral membrane protein ATPase SecA for secretion [
]. The structure of the Escherichia coli SecYEG assembly revealed a sandwich of two membranes interacting through the extensive cytoplasmic domains []. Each membrane is composed of dimers of SecYEG. The monomeric complex contains 15 transmembrane helices. The eubacterial secY protein [
] interacts with the signal sequences of secretory proteins as well as with two other components of the protein translocation system: secA and secE. SecY is an integral plasma membrane protein of 419 to 492 amino acid residues that apparently contains 10 transmembrane (TM), 6 cytoplasmic and 5 periplasmic regions. Cytoplasmic regions 2 and 3, and TM domains 1, 2, 4, 5, 7 and 10 are well conserved: the conserved cytoplasmic regions are believed to interact with cytoplasmic secretion factors, while the TM domains may participate in protein export [
]. Homologs of secY are found in archaebacteria []. SecY is also encoded in the chloroplast genome of some algae [] where it could be involved in a prokaryotic-like protein export system across the two membranes of the chloroplast endoplasmic reticulum (CER) which is present in chromophyte and cryptophyte algae.
The FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane [
]. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton. The FERM domain is located at the N terminus of the majority of FERM-containing proteins [,
], which includes: Band 4.1, which links the spectrin-actin cytoskeleton of erythrocytes to the plasma membrane.Ezrin, a component of the undercoat of the microvilli plasma membrane.Moesin, which is probably involved in binding major cytoskeletal structures to the plasma membrane.Radixin, which is involved in the binding of the barbed end of actin filaments to the plasma membrane in the undercoat of the cell- to-cell adherens junction.Talin, a cytoskeletal protein concentrated in regions of cell-substratum contact and, in lymphocytes, of cell-cell contacts.Filopodin, a slime mold protein that binds actin and which is involved in the control of cell motility and chemotaxis.Merlin (or schwannomin).Protein NBL4.Unconventional myosins X, VIIa and XV, which are mutated in congenital deafness.Focal-adhesion kinases (FAKs), cytoplasmic protein tyrosine kinases involved in signalling through integrins.Janus tyrosine kinases (JAKs), cytoplasmic tyrosine kinases that are non-covalently associated with the cytoplasmic tails of receptors for cytokines or polypeptidic hormones.Non-receptor tyrosine-protein kinase TYK2.Protein-tyrosine phosphatases PTPN3 and PTPN4, enzyme that appear to act at junctions between the membrane and the cytoskeleton.Protein-tyrosine phosphatases PTPN14 and PTP-D1, PTP-RL10 and PTP2E.Caenorhabditis elegans protein phosphatase ptp-1.Ezrin, moesin, and radixin are highly related proteins (ERM protein family), but the other proteins in which the FERM domain is found do not share any region of similarity outside of this domain. ERM proteins are made of three domains, the FERM domain, a central helical domain and a C-terminal tail domain, which binds F-actin. The amino-acid sequence of the FERM domain is highly conserved among ERM proteins and is responsible for membrane association by direct binding to the cytoplasmic domain or tail of integral membrane proteins. ERM proteins are regulated by an intramolecular association of the FERM and C-terminal tail domains that masks their binding sites for other molecules. For cytoskeleton-membrane cross-linking, the dormant molecules becomes activated and the FERM domain attaches to the membrane by binding specific membrane proteins, while the last 34 residues of the tail bind actin filaments. Aside from binding to membranes, the activated FERM domain of ERM proteins can also bind the guanine nucleotide dissociation inhibitor of Rho GTPase (RhoDGI), which suggests that in addition to functioning as a cross-linker, ERM proteins may influence Rho signalling pathways. The crystal structure of the FERM domain reveals that it is composed of three structural modules (F1, F2, and F3) that together form a compact clover-shaped structure [
].The FERM domain has also been called the amino-terminal domain, the 30kDa domain, 4.1N30, the membrane-cytoskeletal-linking domain, the ERM-like domain, the ezrin-like domain of the band 4.1 superfamily, the conserved N-terminal region, and the membrane attachment domain [].This domain is the N-terminal ubiquitin-like structural domain of the FERM domain.
The FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane [
]. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton. The FERM domain is located at the N terminus of the majority of FERM-containing proteins [,
], which includes: Band 4.1, which links the spectrin-actin cytoskeleton of erythrocytes to the plasma membrane.Ezrin, a component of the undercoat of the microvilli plasma membrane.Moesin, which is probably involved in binding major cytoskeletal structures to the plasma membrane.Radixin, which is involved in the binding of the barbed end of actin filaments to the plasma membrane in the undercoat of the cell- to-cell adherens junction.Talin, a cytoskeletal protein concentrated in regions of cell-substratum contact and, in lymphocytes, of cell-cell contacts.Filopodin, a slime mold protein that binds actin and which is involved in the control of cell motility and chemotaxis.Merlin (or schwannomin).Protein NBL4.Unconventional myosins X, VIIa and XV, which are mutated in congenital deafness.Focal-adhesion kinases (FAKs), cytoplasmic protein tyrosine kinases involved in signalling through integrins.Janus tyrosine kinases (JAKs), cytoplasmic tyrosine kinases that are non-covalently associated with the cytoplasmic tails of receptors for cytokines or polypeptidic hormones.Non-receptor tyrosine-protein kinase TYK2.Protein-tyrosine phosphatases PTPN3 and PTPN4, enzyme that appear to act at junctions between the membrane and the cytoskeleton.Protein-tyrosine phosphatases PTPN14 and PTP-D1, PTP-RL10 and PTP2E.Caenorhabditis elegans protein phosphatase ptp-1.Ezrin, moesin, and radixin are highly related proteins (ERM protein family), but the other proteins in which the FERM domain is found do not share any region of similarity outside of this domain. ERM proteins are made of three domains, the FERM domain, a central helical domain and a C-terminal tail domain, which binds F-actin. The amino-acid sequence of the FERM domain is highly conserved among ERM proteins and is responsible for membrane association by direct binding to the cytoplasmic domain or tail of integral membrane proteins. ERM proteins are regulated by an intramolecular association of the FERM and C-terminal tail domains that masks their binding sites for other molecules. For cytoskeleton-membrane cross-linking, the dormant molecules becomes activated and the FERM domain attaches to the membrane by binding specific membrane proteins, while the last 34 residues of the tail bind actin filaments. Aside from binding to membranes, the activated FERM domain of ERM proteins can also bind the guanine nucleotide dissociation inhibitor of Rho GTPase (RhoDGI), which suggests that in addition to functioning as a cross-linker, ERM proteins may influence Rho signalling pathways. The crystal structure of the FERM domain reveals that it is composed of three structural modules (F1, F2, and F3) that together form a compact clover-shaped structure [
].The FERM domain has also been called the amino-terminal domain, the 30kDa domain, 4.1N30, the membrane-cytoskeletal-linking domain, the ERM-like domain, the ezrin-like domain of the band 4.1 superfamily, the conserved N-terminal region, and the membrane attachment domain [
].This entry represents the PH-like domain found at the C terminus of the FERM domain.
The FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) is a widespread protein module involved in localising proteins to the plasma membrane [
]. FERM domains are found in a number of cytoskeletal-associated proteins that associate with various proteins at the interface between the plasma membrane and the cytoskeleton. The FERM domain is located at the N terminus of the majority of FERM-containing proteins [,
], which includes: Band 4.1, which links the spectrin-actin cytoskeleton of erythrocytes to the plasma membrane.Ezrin, a component of the undercoat of the microvilli plasma membrane.Moesin, which is probably involved in binding major cytoskeletal structures to the plasma membrane.Radixin, which is involved in the binding of the barbed end of actin filaments to the plasma membrane in the undercoat of the cell- to-cell adherens junction.Talin, a cytoskeletal protein concentrated in regions of cell-substratum contact and, in lymphocytes, of cell-cell contacts.Filopodin, a slime mold protein that binds actin and which is involved in the control of cell motility and chemotaxis.Merlin (or schwannomin).Protein NBL4.Unconventional myosins X, VIIa and XV, which are mutated in congenital deafness.Focal-adhesion kinases (FAKs), cytoplasmic protein tyrosine kinases involved in signalling through integrins.Janus tyrosine kinases (JAKs), cytoplasmic tyrosine kinases that are non-covalently associated with the cytoplasmic tails of receptors for cytokines or polypeptidic hormones.Non-receptor tyrosine-protein kinase TYK2.Protein-tyrosine phosphatases PTPN3 and PTPN4, enzyme that appear to act at junctions between the membrane and the cytoskeleton.Protein-tyrosine phosphatases PTPN14 and PTP-D1, PTP-RL10 and PTP2E.Caenorhabditis elegans protein phosphatase ptp-1.Ezrin, moesin, and radixin are highly related proteins (ERM protein family), but the other proteins in which the FERM domain is found do not share any region of similarity outside of this domain. ERM proteins are made of three domains, the FERM domain, a central helical domain and a C-terminal tail domain, which binds F-actin. The amino-acid sequence of the FERM domain is highly conserved among ERM proteins and is responsible for membrane association by direct binding to the cytoplasmic domain or tail of integral membrane proteins. ERM proteins are regulated by an intramolecular association of the FERM and C-terminal tail domains that masks their binding sites for other molecules. For cytoskeleton-membrane cross-linking, the dormant molecules becomes activated and the FERM domain attaches to the membrane by binding specific membrane proteins, while the last 34 residues of the tail bind actin filaments. Aside from binding to membranes, the activated FERM domain of ERM proteins can also bind the guanine nucleotide dissociation inhibitor of Rho GTPase (RhoDGI), which suggests that in addition to functioning as a cross-linker, ERM proteins may influence Rho signalling pathways. The crystal structure of the FERM domain reveals that it is composed of three structural modules (F1, F2, and F3) that together form a compact clover-shaped structure [].The FERM domain has also been called the amino-terminal domain, the 30kDa domain, 4.1N30, the membrane-cytoskeletal-linking domain, the ERM-like domain, the ezrin-like domain of the band 4.1 superfamily, the conserved N-terminal region, and the membrane attachment domain [
].This entry represents the conserved sites of the FERM domain.
This superfamily represents a structural domain with a core structure consisting of two layers, alpha/beta. These homologous structural domains can show little sequence identity with each other. A number of mammalian lipid-binding serum glycoproteins contain one or more such structural domains, including:Bactericidal permeability-increasing protein (BPI)Lipopolysaccharide-binding protein (LBP)Cholesteryl ester transfer protein (CETP)Phospholipid transfer protein (PLTP)Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC)Bactericidal permeability-increasing protein (BPI) is a potent antimicrobial protein of 456 residues that binds to and neutralises lipopolysaccharides from the outer membrane of Gram-negative bacteria [
]. BPI contains two domains that adopt the same structural fold, even though they have little sequence similarity []. Lipopolysaccharide-binding protein (LBP) is an endotoxin-binding protein that is closely related to, and functions in a co-ordinated manner with BPI to facilitate an integrated host response to invading Gram-negative bacteria [
].Cholesteryl ester transfer protein (CETP) is a glycoprotein that facilitates the transfer of lipids (cholesteryl esters and triglycerides) between the different lipoproteins that transport them through plasma, including HDL, LDL, VLDL and chylomicrons. These lipoproteins shield the lipids from water by encapsulating them within a coating of polar lipids and proteins [
].Phospholipid transfer protein (PLTP) exchanges phospholipids between lipoproteins and remodels high-density lipoproteins (HDLs) [
].Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC) is a potential host defensive protein that is secreted from the submucosal gland to the saliva and nasal lavage fluid. PLUNC appears to be a secreted product of neutrophil granules that participates in an aspect of the inflammatory response that contributes to host defence [
]. Short palate, lung and nasal epithelium clone 1 (SPLUNC1) may bind the lipopolysaccharide of Gram-negative nanobacteria, thereby playing an important role in the host defence of nasopharyngeal epithelium [].
The AGC (cAMP-dependent, cGMP-dependent and protein kinase C) protein kinase family embraces a collection of protein kinases that display a high degree of sequence similarity within their respective kinase domains. AGC kinase proteins are characterised by three conserved phosphorylation sites that critically regulate their function. The first one is located in an activation loop in the centre of the kinase domain. The two other phosphorylation sites are located outside the kinase domain in a conserved region on its C-terminal side, the AGC-kinase C-terminal domain. These sites serves as phosphorylation-regulated switches to control both intra- and inter-molecular interactions. Without these priming phosphorylations, the kinases are catalytically inactive [
,
,
].Several structures of the AGC-kinase C-terminal domain have been solved. The first phosphorylation site is located in a turn motif, the second one at the end of the domain in an hydrophobic pocket. In PKB the phosphorylated hydrophobic motif engages a hydrophobic groove within the N-lobe of the kinase domain which orders alpha helices close to the active site [
].Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Protein kinases are a group of enzymes that possess a catalytic subunit, which transfers the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues (such as serine, threonine, or tyrosine) in a substrate protein's side chain, resulting in a conformational change affecting protein function. Protein kinase function has been evolutionarily conserved from Escherichia coli to Homo sapiens (Human), where they play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation [].The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [
], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Anti-Mullerian hormone (AMH), also called Mullerian inhibiting substance, is a member of the transforming growth factor beta (TGF-beta) family that represses the development and function of reproductive organs [
]. Anti-Mullerian hormone is thought to exert its effects through two membrane-bound serine/threonine kinase receptors, type 2 and type 1. Upon ligand binding, these drive receptor-specific cytoplasmic substrates, the Smad molecules, into the nucleus where they act as transcription factors. A type 2 receptor specific for AMH was cloned through its homology with receptors of TGF-beta family members. Components of the AMH signalling pathway have been identified in gonads and gonadal cell lines. The AMH type II receptor is highly specific. In contrast, the identity of the AMH type I receptor is not clear.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups [
]:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis [
]. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [
].This entry represents the non-receptor tyrosine kinases SYK and ZAP-70 [
,
,
]:SYK is a positive effector of BCR-stimulated responses. It couples the B-cell antigen receptor (BCR) to the mobilisation of calcium ion, either through a phosphoinositide 3-kinase-dependent pathway (when not phosphorylated on tyrosines of the linker region), or through a phospholipase C-gamma-dependent pathway (when phosphorylated on Tyr-342 and Tyr-346). Therefore, the differential phosphorylation of Syk can determine the pathway by which BCR is coupled to the regulation of intracellular calcium ion [
,
].ZAP70 plays a role in T-cell development and lymphocyte activation. It is essential for TCR-mediated IL-2 production. Isoform 1 of ZAP70 induces TCR-mediated signal transduction, isoform 2 does not [
,
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents predicted serine/threonine-protein kinases (
) such as PknK.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Phosphorylase B kinase (
) belongs to a family of proteins
involved in glycogen biosynthesis []. The protein has a subunit compositionof (alpha, beta, gamma, delta)4, where the alpha and beta subunits are
regulatory, delta is calmodulin, and the gamma subunit is catalytic. The enzyme is believed to have a dual role, the first is connected with glycogen
degradation via phosphorylation of glycogen phosphorylase; the second controls glycogen biosynthesis on the sarcoplasmic reticular membrane more
directly by phosphorylation, and thus inhibition, of glycogen synthase [].The gamma catalytic chain contains three domains; one protein kinase and two
calmodulin-binding domains. Calcium and magnesium ions, together with cyclicAMP, positively affect the efficiency of the enzyme, which is believed to
be associated with its auto-kinase activity [,
].The full extent of the effects of deficiencies in this enzyme in humans is
unknown; but case studies have been documented [,
,
] that detail symptoms asmild as 'exercise intolerance' [
], to infant mortality arising from floppyinfant syndrome [
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents the catalytic domain found in a number of serine/threonine- and tyrosine-protein kinases. It does not include catalytic domain of dual specificity kinases.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents serine/threonine-protein kinases (
), such as Sbk1. Sbk1 may be involved in signal-transduction pathways related to the control of brain development, such as the control of neuronal proliferation or migration in the brain of embryos.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents serine/threonine-protein kinases (
) with pentapeptide domains, such as SpkB from Synechocystis sp. (strain PCC 6803). SpkB is required for cell motility [
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [
].This enry represents a serine/threonine-protein kinase (
) found in Asfivirus such as African swine fever virus (ASFV). These enzymes are essential for viral replication and may mediate the virus' progression through DNA replication [
].
The paired domain is an approximately 126 amino acid DNA-binding domain, which is found in eukaryotic transcription regulatory proteins involved in embryogenesis. The domain was originally described as the 'paired box' in the Drosophila protein paired (prd) [
,
]. The paired domain is generally located in the N-terminal part. An octapeptide [] and/or a homeodomain can occur C-terminal to the paired domain, as well as a Pro-Ser-Thr-rich C terminus.Paired domain proteins can function as transcription repressors or activators. The paired domain contains three subdomains, which show functional differences in DNA-binding. The crystal structures of prd and Pax proteins show that the DNA-bound paired domain is bipartite, consisting of an N-terminal subdomain (PAI or NTD) and a C-terminal subdomain (RED or CTD), connected by a linker. PAI and RED each form a three-helical fold, with the most C-terminal helices comprising a helix-turn-helix (HTH) motif that binds the DNA major groove. In addition, the PAI subdomain encompasses an N-terminal β-turn and
β-hairpin, also named 'wing', participating in DNA-binding. The linker canbind into the DNA minor groove. Different Pax proteins and their alternatively
spliced isoforms use different (sub)domains for DNA-binding to mediate thespecificity of sequence recognition [
,
].Some proteins known to contain a paired domain:Drosophila paired (prd), a segmentation pair-rule class protein.Drosophila gooseberry proximal (gsb-p) and gooseberry distal (gsb-d),
segmentation polarity class proteins.Drosophila Pox-meso and Pox-neuro proteins.The Pax proteins:Mammalian protein Pax1, which may play a role in the formation of segmented structures in the embryo. In mouse, mutations in Pax1 produce the undulated phenotype, characterised by vertebral malformations along the entire rostro-caudal axis.Mammalian protein Pax2, a probable transcription factor that may have a
role in kidney cell differentiation.Mammalian protein Pax3. Pax3 is expressed during early neurogenesis. In humans, defects in Pax3 are the cause of Waardenburg's syndrome (WS), an
autosomal dominant combination of deafness and pigmentary disturbance.Mammalian protein Pax4 pays an important role in the differentiation and development of pancreatic islet beta cells. It binds to a common element in the glucagon, insulin and somatostatin promoters. In humans, it has been related to the rare, familial, clinically and genetically heterogeneous form of diabetes MODY (maturity-onset diabetes of the young).Mammalian protein Pax5, also known as B-cell specific transcription factor
(BSAP). Pax5 is involved in the regulation of the CD19 gene. It plays animportant role in B-cell differentiation as well as neural development and
spermatogenesis.Mammalian protein Pax6 (oculorhombin). Pax6 is a transcription factor with
important functions in eye and nasal development. In Man, defects in Pax6are the cause of aniridia type II (AN2), an autosomal dominant disorder
characterised by complete or partial absence of the iris.Mammalian protein Pax7 is involved in the regulation of muscle stem cells proliferation, playing a role in myogenesis and muscle regeneration.Mammalian protein Pax8, required in thyroid development.Mammalian protein Pax9, required for normal development of thymus, parathyroid glands, ultimobranchial bodies, teeth, skeletal elements of skull and larynx as well as distal limbs. In man, defects in Pax9 cause oligodontia.Zebrafish protein Paired box protein Pax-2a, involved in the development of the midbrain/hindbrain boundary organizer and specification of neuronal cell fates.Xenopus laevis protein Paired box protein Pax-3-A, which promotes both hatching gland and neural crest cell fates, two of the cell populations that arise from the neural plate border.
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans [
]. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes [
]. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 [
]. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope. Active cell suicide (apoptosis) is induced by events such as growth factor withdrawal and toxins. It is controlled by regulators, which have either an inhibitory effect on programmed cell death (anti-apoptotic) or block the protective effect of inhibitors (pro-apoptotic) [
,
]. Many viruses have found a way of countering defensive apoptosis by encoding their own anti-apoptosis genes preventing their target-cells from dying too soon. All proteins belonging to the Bcl-2 family [
] contain either a BH1, BH2, BH3, or BH4 domain. All anti-apoptoticproteins contain BH1 and BH2 domains, some of them contain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L), Bcl-w), which is never seen in pro-apoptotic proteins, except for Bcl-x(S). On the other hand, all pro-apoptotic proteins contain a BH3 domain (except for Bad) necessary for
dimerisation with other proteins of Bcl-2 family and crucial for their killing activity, some of them also contain BH1 and BH2 domains (Bax, Bak). The BH3 domain is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L). Proteins that are known to contain these domains include vertebrateBcl-2 (alpha and beta isoforms) and Bcl-x (isoforms (Bcl-x(L) and Bcl-x(S)); mammalian proteins Bax and Bak; mouse protein Bid; Xenopus laevis proteins Xr1 and Xr11; human induced myeloid leukemia cell
differentiation protein MCL1 and Caenorhabditis elegans protein ced-9.
This entry represents the S-100 domain. Proteins containing this domain are belonging to the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins [
,
,
]. Many S100 proteins have been found to bind transition metals, such as Zn2+ and Cu2+ []. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets [
]. In addition to S100 proteins, this group includes the 'fused' gene family, a group of calcium binding S100-related proteins. The 'fused' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin [
], hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These 'fused' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, 'fused' gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents the salt-inducible protein kinases, SIK1 and SIK2, which are serine/threonine-protein kinases primarily activated by the master kinase LKB1 (STK11). SIK1 is involved in a variety of processes, such as cell cycle regulation, gluconeogenesis and lipogenesis regulation and muscle growth [
,
,
,
]. SIK2 phosphorylates insulin receptor substrate-1 (IRS1) in insulin-stimulated adipocytes, potentially modulating the efficiency of insulin signal transduction, and may have a role in the development of insulin resistance in diabetes [. SIK1/2 inhibit CREB activity by phosphorylating and inhibiting activity of TORCs, the CREB-specific coactivators, like CRTC2/TORC2 and CRTC3/TORC3 in response to cAMP signalling [
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This represents serine/threonine-protein kinases (
), such as Ulk1 and Ulk2 (Unc-51-Like Kinase). Ulk1 and Ulk2 regulate filopodia extension and branching of sensory axons. They are important for axon growth, playing an essential role in neurite extension of cerebellar granule cells [
, ].
A conserved domain of about 70 amino acids has been found in prokaryotic and eukaryotic single-strand nucleic-acid binding proteins [
,
,
,
,
]. This domain, which is known as the 'cold-shock domain' (CSD) is present in the proteins listed below.Escherichia coli protein CS7.4 (gene cspA) which is induced in response to low temperature (cold-shock protein) and which binds to and stimulates the transcription of the CCAAT-containing promoters of the HN-S protein and of gyrA.Transcription termination factor Rho, a prokaryotic protein which facilitates transcription termination.Mammalian Y box binding protein 1 (YB1). A protein that binds to the CCAAT-containing Y box of mammalian HLA class II genes.Xenopus Y box binding proteins -1 and -2 (Y1 and Y2). Proteins that bind to the CCAAT-containing Y box of Xenopus hsp70 genes.Xenopus B box binding protein (YB3). YB3 binds the B box promoter element of genes transcribed by RNA polymerase III.Enhancer factor I subunit A (EFI-A) (dbpB). A protein that also bind to CCAAT-motif in various gene promoters.DbpA, a human DNA-binding protein of unknown specificity.Bacillus subtilis cold-shock proteins cspB and cspC.Streptomyces clavuligerus protein SC 7.0.E. coli proteins cspB, cspC, cspD, cspE and cspF.Unr, a mammalian gene encoded upstream of the N-ras gene. Unr contains nine repeats that are similar to the CSD domain. The function of Unr is not yet known but it could be a multivalent DNA-binding protein.PPPin, a mammalian brain-specific protein that binds to histone mRNA and which is thought to play a role in the regulation of brain development.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity [
]:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents 3-deoxy-D-manno-octulosonic acid kinase, which is responsible for the ATP-dependent phosphorylation of 3-deoxy-D-manno-octulosonic acid at the 4-OH position during lipopolysaccharide core biosynthesis.
This entry represents a conserved region found in several lipid transport proteins, including vitellogenin, microsomal triglyceride transfer protein and apolipoprotein B-100 [
].Vitellinogen precursors provide the major egg yolk proteins that are a source of nutrients during early development of oviparous vertebrates and invertebrates. Vitellinogen precursors are multi-domain apolipoproteins that are cleaved into distinct yolk proteins. Different vitellinogen precursors exist, which are composed of variable combinations of yolk protein components; however, the cleavage sites are conserved. In vertebrates, a complete vitellinogen is composed of an N-terminal signal peptide for export, followed by four regions that can be cleaved into yolk proteins: lipovitellin-1, phosvitin, lipovitellin-2, and a von Willebrand factor type D domain (YGP40) [
,
].Microsomal triglyceride transfer protein (MTTP) is an endoplasmic reticulum lipid transfer protein involved in the biosynthesis and lipid loading of apolipoprotein B. MTTP is also involved in the late stage of CD1d trafficking in the lysosomal compartment, CD1d being the MHC I-like lipid antigen presenting molecule [].Apolipoprotein B can exist in two forms: B-100 and B-48. Apoliporotein B-100 is present on several lipoproteins, including very low-density lipoproteins (VLDL), intermediate density lipoproteins (IDL) and low density lipoproteins (LDL), and can assemble VLDL particles in the liver [
]. Apolipoprotein B-100 has been linked to the development of atherosclerosis.
The CHROMO (CHRromatin Organization MOdifier) domain [
,
,
,
] is a conserved region of around 60 amino acids, originally identified in Drosophila modifiers of variegation. These are proteins that alter the structure of chromatin to the condensed morphology of heterochromatin, a cytologically visible condition where gene expression is repressed. In one of these proteins, Polycomb, the chromo domain has been shown to be important for chromatin targeting.
Proteins that contain a chromo domain appear to fall into 3 classes. The first class includes proteins having an N-terminal chromo domain
followed by a region termed the chromo shadow domain, with weak but significant sequence similarity to the N-terminal chromo domain [], eg. Drosophila and human heterochromatin protein Su(var)205 (HP1). The second class includes proteins with
a single chromo domain, eg. Drosophila protein Polycomb (Pc); mammalian modifier 3; human Mi-2 autoantigen and several yeast and Caenorhabditis elegans hypothetical proteins. In the third class paired tandem chromo domains are found, eg. in mammalian DNA-binding/helicase proteins CHD-1 to CHD-4 and yeast protein CHD1.Functional dissections of chromo domain proteins suggests a mechanistic role for chromo domains in targeting chromo domain proteins to specific regions of the nucleus. The mechanism of targeting may involve protein-protein and/or protein/nucleic acid interactions. Hence, several line of evidence show that the HP1 chromo domain is a methyl-specific histone binding module, whereas the chromo domain of two protein components of the drosophila dosage compensation complex, MSL3 and MOF, contain chromo domains that bind to RNA in vitro [
].The high resolution structures of HP1-family protein chromo and chromo shadow domain reveal a conserved chromo domain fold motif consisting of three β-strands packed against an α-helix. The chromo domain fold belongs to the OB (oligonucleotide/oligosaccharide binding)-fold class found in a variety of prokaryotic and eukaryotic nucleic acid binding protein [
].This entry represents a conserved site in the chromo domain.
The CHROMO (CHRromatin Organization MOdifier) domain [
,
,
,
] is a conserved region of around 60 amino acids, originally identified in Drosophila modifiers of variegation. These are proteins that alter the structure of chromatin to the condensed morphology of heterochromatin, a cytologically visible condition where gene expression is repressed. In one of these proteins, Polycomb, the chromo domain has been shown to be important for chromatin targeting.
Proteins that contain a chromo domain appear to fall into 3 classes. The first class includes proteins having an N-terminal chromo domain followed by a region termed the chromo shadow domain, with weak but significant sequence similarity to the N-terminal chromo domain [
], eg. Drosophila and human heterochromatin protein Su(var)205 (HP1). The second class includes proteins with
a single chromo domain, eg. Drosophila protein Polycomb (Pc); mammalian modifier 3; human Mi-2 autoantigen and several yeast and Caenorhabditis elegans hypothetical proteins. In the third class paired tandem chromo domains are found, eg. in mammalian DNA-binding/helicase proteins CHD-1 to CHD-4 and yeast protein CHD1.Functional dissections of chromo domain proteins suggests a mechanistic role for chromo domains in targeting chromo domain proteins to specific regions of the nucleus. The mechanism of targeting may involve protein-protein and/or protein/nucleic acid interactions. Hence, several line of evidence show that the HP1 chromo domain is a methyl-specific histone binding module, whereas the chromo domain of two protein components of the drosophila dosage compensation complex, MSL3 and MOF, contain chromo domains that bind to RNA in vitro [
].The high resolution structures of HP1-family protein chromo and chromo shadow domain reveal a conserved chromo domain fold motif consisting of three β-strands packed against an α-helix. The chromo domain fold belongs to the OB (oligonucleotide/oligosaccharide binding)-fold class found in a variety of prokaryotic and eukaryotic nucleic acid binding protein [
].
The CHROMO (CHRromatin Organization MOdifier) domain [
,
,
,
] is a conserved region of around 60 amino acids, originally identified in Drosophila modifiers of variegation. These are proteins that alter the structure of chromatin to the condensed morphology of heterochromatin, a cytologically visible condition where gene expression is repressed. In one of these proteins, Polycomb, the chromo domain has been shown to be important for chromatin targeting.
Proteins that contain a chromo domain appear to fall into 3 classes. The first class includes proteins having an N-terminal chromo domain
followed by a region termed the chromo shadow domain, with weak but significant sequence similarity to the N-terminal chromo domain [], eg. Drosophila and human heterochromatin protein Su(var)205 (HP1). The second class includes proteins with
a single chromo domain, eg. Drosophila protein Polycomb (Pc); mammalian modifier 3; human Mi-2 autoantigen and several yeast and Caenorhabditis elegans hypothetical proteins. In the third class paired tandem chromo domains are found, eg. in mammalian DNA-binding/helicase proteins CHD-1 to CHD-4 and yeast protein CHD1.Functional dissections of chromo domain proteins suggests a mechanistic role for chromo domains in targeting chromo domain proteins to specific regions of the nucleus. The mechanism of targeting may involve protein-protein and/or protein/nucleic acid interactions. Hence, several line of evidence show that the HP1 chromo domain is a methyl-specific histone binding module, whereas the chromo domain of two protein components of the drosophila dosage compensation complex, MSL3 and MOF, contain chromo domains that bind to RNA in vitro [
].The high resolution structures of HP1-family protein chromo and chromo shadow domain reveal a conserved chromo domain fold motif consisting of three β-strands packed against an α-helix. The chromo domain fold belongs to the OB (oligonucleotide/oligosaccharide binding)-fold class found in a variety of prokaryotic and eukaryotic nucleic acid binding protein [
].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human [
]. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents the lipopolysaccharide core heptose(I) kinase RfaP, which is required for the addition of phosphate to O-4 of the first heptose residue of the lipopolysaccharide (LPS) inner core region. It has previously been shown that RfaP is necessary for resistance to hydrophobic and polycationic antimicrobials in Escherichia coli, and that it is required for virulence in invasive strains of S. enterica [
].
SecA is a DEAD-like helicase belonging to superfamily SF2, a diverse family of proteins involved in ATP-dependent RNA or DNA unwinding. SecA helicase core consists of two similar protein domains that resemble the fold of the recombination protein RecA. This entry represents the C-terminal domain, also called HelicC [].Secretion across the inner membrane in some Gram-negative bacteria occurs via the preprotein translocase pathway. Proteins are produced in the cytoplasm as precursors, and require a chaperone subunit to direct them to the translocase component [
]. From there, the mature proteins are either targeted to the outer membrane, or remain as periplasmic proteins. The translocase protein subunits are encoded on the bacterial chromosome.The translocase itself comprises 7 proteins, including a chaperone protein (SecB), an ATPase (SecA), an integral membrane complex (SecCY, SecE and SecG), and two additional membrane proteins that promote the release of the mature peptide into the periplasm (SecD and SecF) [
]. The chaperone protein SecB [] is a highly acidic homotetrameric protein that exists as a "dimer of dimers"in the bacterial cytoplasm. SecB maintains preproteins in an unfolded state after translation, and targets these to the peripheral membrane protein ATPase SecA for secretion [
].SecA is a cytoplasmic protein of 800 to 960 amino acid residues. Homologues of secA are also encoded in the chloroplast genome of some algae [
] as well as in the nuclear genome of plants []. It could be involved in the intraorganellar protein transport into thylakoids.
Secretion across the inner membrane in some Gram-negative bacteria occurs via the preprotein translocase pathway. Proteins are produced in the cytoplasm as precursors, and require a chaperone subunit to direct them to the translocase component [
]. From there, the mature proteins are either targeted to the outer membrane, or remain as periplasmic proteins. The translocase protein subunits are encoded on the bacterial chromosome.
The translocase itself comprises 7 proteins, including a chaperone protein (SecB), an ATPase (SecA), an integral membrane complex (SecY, SecE and SecG), and two additional membrane proteins that promote the release of the mature peptide into the periplasm (SecD and SecF) [
]. The chaperone protein SecB [] is a highly acidic homotetrameric protein that exists as a "dimer of dimers"in the bacterial cytoplasm. SecB maintains preproteins in an unfolded state after translation, and targets these to the peripheral membrane protein ATPase SecA for secretion [
]. The structure of the Escherichia coli SecYEG assembly revealed a sandwich of two membranes interacting through the extensive cytoplasmic domains []. Each membrane is composed of dimers of SecYEG. The monomeric complex contains 15 transmembrane helices. The eubacterial secY protein [
] interacts with the signal sequences of secretory proteins as well as with two other components of the protein translocation system: secA and secE. SecY is an integral plasma membrane protein of 419 to 492 amino acid residues that apparently contains 10 transmembrane (TM), 6 cytoplasmic and 5 periplasmic regions. Cytoplasmic regions 2 and 3, and TM domains 1, 2, 4, 5, 7 and 10 are well conserved: the conserved cytoplasmic regions are believed to interact with cytoplasmic secretion factors, while the TM domains may participate in protein export [
]. Homologs of secY are found in archaebacteria []. SecY is also encoded in the chloroplast genome of some algae [] where it could be involved in a prokaryotic-like protein export system across the two membranes of the chloroplast endoplasmic reticulum (CER) which is present in chromophyte and cryptophyte algae.This superfamily represents the structural domain of SecY [
].
A number of actin-binding proteins, including spectrin, alpha-actinin and fimbrin, contain a 250 amino acid stretch called the actin binding domain
(ABD). The ABD has probably arisen from duplication of a domain which is also found in a single copy in a number of other proteins like calponin or the vav proto-oncogene and has been called calponin homology (CH) domain [,
].A detailed analysis of The CH domain-containing proteins has shown that they can be divided in three groups [
]:The fimbrin family of monomeric actin cross-linking molecules containing two ABDsDimeric cross-linking proteins (alpha-actinin, beta-spectrin, filamin, etc.) and monomeric F-actin binding proteins (dystrophin, utrophin) each containing one ABDProteins containing only a single amino terminal CH domain. Each single ABD, comprising two CH domains, is able to bind one actin monomer in the filament. The N-terminal CH domain has the intrinsic ability tobind actin, albeit with lower affinity than the complete ABD, whereas the C-terminal CH bind actin extremely weakly or not at all. Nevertheless
both CH domains are required for a fully functional ABD; the C-terminal CH domain contributing to the overall stability of the complete ABD throughinter-domain helix-helix interactions [
]. Some of the proteins containing a single CH domain also bind to actin, although this has not been shown to be via the single CH domain alone []. In addition, the CH domain occurs also in a number of proteins not known to bind actin, a notable example being the vav protooncogene.The resolution of the 3D structure of various CH domains has shown that the conserved core consist of four major α-helices [
].Proteins containing a calponin domain include:Calponin, which is involved in the regulation of contractility and organisation of the actin cytoskeleton in smooth muscle cells [
].Beta-spectrin, a major component of a submembrane cytoskeletal network connecting actin filaments to integral plasma membrane proteins [
].The actin-cross-linking domain of the fimbrin/plastin family of actin filament bundling or cross-linking proteins [
].Utrophin,a close homologue of dystrophin [
].Dystrophin, the protein found to be defective in Duchenne muscular dystrophy; this protein contains a tandem repeat of two CH domains [
].Actin-binding domain of plectin, a large and widely expressed cytolinker protein [
].The N-terminal microtubule-binding domain of microtubule-associated protein eb1 (end-binding protein), a member of a conserved family of proteins that localise to the plus-ends of microtubules [
].Ras GTPase-activating-like protein rng2, an IQGAP protein that is essential for the assembly of an actomyosin ring during cytokinesis [
].Transgelin, which suppresses androgen receptor transactivation [
].
A number of actin-binding proteins, including spectrin, alpha-actinin and fimbrin, contain a 250 amino acid stretch called the actin binding domain
(ABD). The ABD has probably arisen from duplication of a domain which is also found in a single copy in a number of other proteins like calponin or the vav proto-oncogene and has been called calponin homology (CH) domain [,
].A detailed analysis of The CH domain-containing proteins has shown that they can be divided in three groups [
]:The fimbrin family of monomeric actin cross-linking molecules containing two ABDsDimeric cross-linking proteins (alpha-actinin, beta-spectrin, filamin, etc.) and monomeric F-actin binding proteins (dystrophin, utrophin) each containing one ABDProteins containing only a single amino terminal CH domain. Each single ABD, comprising two CH domains, is able to bind one actin monomer in the filament. The N-terminal CH domain has the intrinsic ability tobind actin, albeit with lower affinity than the complete ABD, whereas the C-terminal CH bind actin extremely weakly or not at all. Nevertheless
both CH domains are required for a fully functional ABD; the C-terminal CH domain contributing to the overall stability of the complete ABD throughinter-domain helix-helix interactions [
]. Some of the proteins containing a single CH domain also bind to actin, although this has not been shown to be via the single CH domain alone []. In addition, the CH domain occurs also in a number of proteins not known to bind actin, a notable example being the vav protooncogene.The resolution of the 3D structure of various CH domains has shown that the conserved core consist of four major α-helices [
].Proteins containing a calponin domain include:Calponin, which is involved in the regulation of contractility and organisation of the actin cytoskeleton in smooth muscle cells [
].Beta-spectrin, a major component of a submembrane cytoskeletal network connecting actin filaments to integral plasma membrane proteins [
].The actin-cross-linking domain of the fimbrin/plastin family of actin filament bundling or cross-linking proteins [
].Utrophin,a close homologue of dystrophin [
].Dystrophin, the protein found to be defective in Duchenne muscular dystrophy; this protein contains a tandem repeat of two CH domains [
].Actin-binding domain of plectin, a large and widely expressed cytolinker protein [
].The N-terminal microtubule-binding domain of microtubule-associated protein eb1 (end-binding protein), a member of a conserved family of proteins that localise to the plus-ends of microtubules [
].Ras GTPase-activating-like protein rng2, an IQGAP protein that is essential for the assembly of an actomyosin ring during cytokinesis [
].Transgelin, which suppresses androgen receptor transactivation [
].
The Nucleocapsid (N) protein is a highly immunogenic phosphoprotein also implicated in viral genome replication and in modulating cell signalling pathways. The N protein interacts with genomic and subgenomic RNA molecules. Together with the envelope protein M, it participates in genome condensation and packaging. The N protein is a highly immunogenic and abundantly expressed protein during infection, capable of inducing protective immune responses against SARS-CoV and SARS-CoV-2 [
,
,
,
,
].Coronavirus (CoV) nucleocapsid (N) proteins have 3 highly conserved domains. The N-terminal domain (NTD) (N1b), the C-terminal domain (CTD)(N2b) and the N3 region. The N1b and N2b domains from SARS CoV, infectious bronchitis virus (IBV), human CoV 229E and mouse hepatic virus (MHV) display similar topological organisations. N proteins form dimers, which are asymmetrically arranged into octamers via their N2b domains.Domains N1b and N2b are linked by another domain N2a that contains an SR-rich region (rich in serine and arginine residues). A priming phosphorylation of specific serine residues by an as yet unknown kinase, triggers the subsequent phosphorylation by the host glycogen synthase kinase-3 (GSK-3) of several residues in the SR-rich region. This phosphorylation allows the N protein to associate with the RNA helicase DDX1 permitting template read-through, and enabling the transition from discontinuous transcription of subgenomic mRNAs (sgmRNAs) to continuous synthesis of longer sgmRNAs and genomic RNA (gRNA). Production of gRNA in the presence of N oligomers may promote the formation of ribonucleoprotein complexes, and the newly transcribed sgmRNA would guarantee efficient synthesis of structural proteins [
,
,
].It has been shown that N proteins interact with nonstructural protein 3 (NSP3) and thus are recruited to the replication-transcription complexes (RTCs). In MHV, the N1b and N2a domains mediate the binding to NSP3 in a gRNA-independent manner. At the RTCs, the N protein is required for the stimulation of gRNA replication and sgmRNA transcription. It remains unclear, however, how and why the N protein orchestrates viral RNA synthesis. The cytoplasmic N-terminal ubiquitin-like domain of NSP3 and the SR-rich region of the N2a domain of the N protein may be important for this interaction. The direct association of N protein with RTCs is a critical step for MHV infection [
].This entry represents the nucleocapsid protein from gammacoronavirus.
The Nucleocapsid (N) protein is a highly immunogenic phosphoprotein also implicated in viral genome replication and in modulating cell signalling pathways. The N protein interacts with genomic and subgenomic RNA molecules. Together with the envelope protein M, it participates in genome condensation and packaging. The N protein is a highly immunogenic and abundantly expressed protein during infection, capable of inducing protective immune responses against SARS-CoV and SARS-CoV-2 [
,
,
,
,
].Coronavirus (CoV) nucleocapsid (N) proteins have 3 highly conserved domains. The N-terminal domain (NTD) (N1b), the C-terminal domain (CTD)(N2b) and the N3 region. The N1b and N2b domains from SARS CoV, infectious bronchitis virus (IBV), human CoV 229E and mouse hepatic virus (MHV) display similar topological organisations. N proteins form dimers, which are asymmetrically arranged into octamers via their N2b domains.Domains N1b and N2b are linked by another domain N2a that contains an SR-rich region (rich in serine and arginine residues). A priming phosphorylation of specific serine residues by an as yet unknown kinase, triggers the subsequent phosphorylation by the host glycogen synthase kinase-3 (GSK-3) of several residues in the SR-rich region. This phosphorylation allows the N protein to associate with the RNA helicase DDX1 permitting template read-through, and enabling the transition from discontinuous transcription of subgenomic mRNAs (sgmRNAs) to continuous synthesis of longer sgmRNAs and genomic RNA (gRNA). Production of gRNA in the presence of N oligomers may promote the formation of ribonucleoprotein complexes, and the newly transcribed sgmRNA would guarantee efficient synthesis of structural proteins [
,
,
].It has been shown that N proteins interact with nonstructural protein 3 (NSP3) and thus are recruited to the replication-transcription complexes (RTCs). In MHV, the N1b and N2a domains mediate the binding to NSP3 in a gRNA-independent manner. At the RTCs, the N protein is required for the stimulation of gRNA replication and sgmRNA transcription. It remains unclear, however, how and why the N protein orchestrates viral RNA synthesis. The cytoplasmic N-terminal ubiquitin-like domain of NSP3 and the SR-rich region of the N2a domain of the N protein may be important for this interaction. The direct association of N protein with RTCs is a critical step for MHV infection [
].This entry represents the nucleocapsid protein from alphacoronavirus.
The Nucleocapsid (N) protein is a highly immunogenic phosphoprotein also implicated in viral genome replication and in modulating cell signalling pathways. The N protein interacts with genomic and subgenomic RNA molecules. Together with the envelope protein M, it participates in genome condensation and packaging. The N protein is a highly immunogenic and abundantly expressed protein during infection, capable of inducing protective immune responses against SARS-CoV and SARS-CoV-2 [,
,
,
,
].Coronavirus (CoV) nucleocapsid (N) proteins have 3 highly conserved domains. The N-terminal domain (NTD) (N1b), the C-terminal domain (CTD)(N2b) and the N3 region. The N1b and N2b domains from SARS CoV, infectious bronchitis virus (IBV), human CoV 229E and mouse hepatic virus (MHV) display similar topological organisations. N proteins form dimers, which are asymmetrically arranged into octamers via their N2b domains.Domains N1b and N2b are linked by another domain N2a that contains an SR-rich region (rich in serine and arginine residues). A priming phosphorylation of specific serine residues by an as yet unknown kinase, triggers the subsequent phosphorylation by the host glycogen synthase kinase-3 (GSK-3) of several residues in the SR-rich region. This phosphorylation allows the N protein to associate with the RNA helicase DDX1 permitting template read-through, and enabling the transition from discontinuous transcription of subgenomic mRNAs (sgmRNAs) to continuous synthesis of longer sgmRNAs and genomic RNA (gRNA). Production of gRNA in the presence of N oligomers may promote the formation of ribonucleoprotein complexes, and the newly transcribed sgmRNA would guarantee efficient synthesis of structural proteins [
,
,
].It has been shown that N proteins interact with nonstructural protein 3 (NSP3) and thus are recruited to the replication-transcription complexes (RTCs). In MHV, the N1b and N2a domains mediate the binding to NSP3 in a gRNA-independent manner. At the RTCs, the N protein is required for the stimulation of gRNA replication and sgmRNA transcription. It remains unclear, however, how and why the N protein orchestrates viral RNA synthesis. The cytoplasmic N-terminal ubiquitin-like domain of NSP3 and the SR-rich region of the N2a domain of the N protein may be important for this interaction. The direct association of N protein with RTCs is a critical step for MHV infection [
].This entry represents the nucleocapsid protein from Betacoronavirus.
The Nucleocapsid (N) protein is a highly immunogenic phosphoprotein also implicated in viral genome replication and in modulating cell signalling pathways. The N protein interacts with genomic and subgenomic RNA molecules. Together with the envelope protein M, it participates in genome condensation and packaging. The N protein is a highly immunogenic and abundantly expressed protein during infection, capable of inducing protective immune responses against SARS-CoV and SARS-CoV-2 [
,
,
,
,
].Coronavirus (CoV) nucleocapsid (N) proteins have 3 highly conserved domains. The N-terminal domain (NTD) (N1b), the C-terminal domain (CTD)(N2b) and the N3 region. The N1b and N2b domains from SARS CoV, infectious bronchitis virus (IBV), human CoV 229E and mouse hepatic virus (MHV) display similar topological organisations. N proteins form dimers, which are asymmetrically arranged into octamers via their N2b domains.Domains N1b and N2b are linked by another domain N2a that contains an SR-rich region (rich in serine and arginine residues). A priming phosphorylation of specific serine residues by an as yet unknown kinase, triggers the subsequent phosphorylation by the host glycogen synthase kinase-3 (GSK-3) of several residues in the SR-rich region. This phosphorylation allows the N protein to associate with the RNA helicase DDX1 permitting template read-through, and enabling the transition from discontinuous transcription of subgenomic mRNAs (sgmRNAs) to continuous synthesis of longer sgmRNAs and genomic RNA (gRNA). Production of gRNA in the presence of N oligomers may promote the formation of ribonucleoprotein complexes, and the newly transcribed sgmRNA would guarantee efficient synthesis of structural proteins [
,
,
].It has been shown that N proteins interact with nonstructural protein 3 (NSP3) and thus are recruited to the replication-transcription complexes (RTCs). In MHV, the N1b and N2a domains mediate the binding to NSP3 in a gRNA-independent manner. At the RTCs, the N protein is required for the stimulation of gRNA replication and sgmRNA transcription. It remains unclear, however, how and why the N protein orchestrates viral RNA synthesis. The cytoplasmic N-terminal ubiquitin-like domain of NSP3 and the SR-rich region of the N2a domain of the N protein may be important for this interaction. The direct association of N protein with RTCs is a critical step for MHV infection [
].The entry represents the Coronavirus nucleocapsid protein.
ATP binding cassette (ABC) transporters are a ubiquitous family of importer
and exporter proteins that consist of two α-helical transmembrane (TM)domains, which form a translocation pathway, and two cytoplasmic ABC domains,
which power the transport reaction through binding and hydrolysis of ATP. In addition most bacterial importers employs a periplasmic substrate-binding protein (PBP) that delivers the ligand to the extracellular gate of the TM domains. These proteins bind their substrates selectively and with high affinity, which is thought to ensure the specificity of the transport reaction. Binding proteins in Gram-negative bacteria are present within the periplasm, whereas those in Gram-positive bacteria are tethered to the cell membrane via the acylation of a cysteine residue that is an integral component of a lipoprotein signal sequence. The cobalamin (vitamin B12) and the iron transport systems share many common attributes and probably evolved from the same origin [,
,
].The structure of the periplasmic-binding domain is composed of two subdomains,each consisting of a central β-sheet and surrounding α-helices, linked
by a rigid α-helix. The substrate binding site is located in a cleft between the two alpha/beta subdomains [].Some protein known to contain an iron siderophore/cobalamin periplasmic-
binding domain are listed below:Escherichia coli vitamin B12 transport protein btuF. It is the periplasmic
binding protein for the vitamin B12 transporter btuCD.Escherichia coli ferrichrome-binding periplasmic protein (fhuD). It binds
iron(III)-hydroxamates.Staphylococcus aureus ferric hydroxamate receptor 2 (fhuD2).Escherichia coli ferrienterobactin-binding periplasmic protein fepB. It binds ferrienterobactin; part of the binding-protein-dependent transport system for uptake of ferrienterobactin.Vibrio cholerae periplasmic binding protein (viuP).Escherichia coli iron(III) dicitrate-binding periplasmic protein (fecB). It binds citrate-dependent iron(III); part of the binding-protein-dependent transport system for uptake of citrate-dependent iron(III).Erwinia chrysanthemi achromobactin-binding periplasmic protein (cbrA). It binds citrate-or chloride-dependent iron(III); part of the binding-protein-dependent transport system cbrABCD for uptake of the siderophore achromobactin.Yersinia pestis hemin-binding periplasmic protein (hmuT).
Solute-binding protein family 5 consists of peptide and nickel-binding proteins [
]. MppA, a member of this family, is essential for import of the bacterial cell wall peptide L-alanyl-gamma-D-glutamyl-meso-diaminopimelate []. GsiB (YliB) is a glutathione-binding protein []. XP55 from Streptomyces lividans is one additional protein of unknown function that belongs to this group [].Proteins in this entry include:Periplasmic oligopeptide-binding proteins (oppA) of Gram-negative bacteria and homologous lipoproteins in Gram-positive bacteria (oppA, amiA or appA)Periplasmic dipeptide-binding proteins of Escherichia coli (dppA) and Bacillus subtilis (dppE)Periplasmic murein peptide-binding protein of E. coli (mppA) Periplasmic peptide-binding proteins sapA of E. coli, Salmonella typhimurium and Haemophilus influenzaePeriplasmic nickel-binding protein (nikA) of E. coliHaem-binding lipoprotein (hbpA or dppA) from H. influenzaeLipoprotein xP55 from Streptomyces lividansMetal-staphylopine-binding protein CntA from Staphylococcus aureus. Hypothetical proteins from H. influenzae (HI0213) and Rhizobium sp. (strain NGR234) symbiotic plasmid (y4tO and y4wM)
This entry represents the RNA recognition motif 1 (RRM1) of type I poly(A)-binding proteins (PABPs).
Poly(A)-binding proteins (PABPs) are highly conserved proteins that bind to the poly(A) tail present at the 3' ends of most eukaryotic mRNAs [
]. These highly conserved proteins are found only in eukaryotes; single-celled eukaryotes each have a single PABP, whereas humans have five and Arabidopis has eight. In humans, three lineages of PABP proteins are observed: cytoplasmic PABPs (PABPC1, PABPC3, and iPABP); nuclear PABP (PABPN1); and X-linked PABP (PABPC5) []. The mammalian PABPs contain four RNA recognition motifs (RRMs). RRM 1 and 2 are primarily responsible for the high-affinity binding to homopolymeric adenosines, while RRMs 3 and 4 can bind to nonhomopolymeric AU sequences []. Proteins containing this motif include:Polyadenylate-binding protein 1 (PABP-1 or PABPC1): PABP-1 is the major cytoplasmic PABP isoform in adult mouse somatic cells. It is able to bind
simultaneously to the cap-binding complex subunit eIF4G and to the poly(A) tail. Therefore, it has been suggested to play a role in altering the structure and/or function of the translation termination complex. It may have additional functions within the eukaryotic mRNA transcriptome. PABP-1 possesses an A-rich sequence in its 5'-UTR and allows binding of PABP and blockage of translation of its own mRNA []. Polyadenylate-binding protein 3 (PABP-3 or PABPC3): PABP-3 is a testis-specific poly(A)-binding protein specifically expressed in round spermatids. It is mainly found in mammalian and may play an important role in the testis-specific regulation of mRNA homeostasis. PABP-3 shows significant sequence similarity to PABP-1. However, it binds to poly(A) with a lower affinity than PABP-1. Dislike PABP-1, PABP-3 lacks the A-rich sequence in its 5'-UTR [
]. Polyadenylate-binding protein 4 (PABP-4 or APP-1 or iPABP): PABP-4 is an inducible poly(A)-binding protein (iPABP) that is primarily localized to the cytoplasm.
It shows significant sequence similarity to PABP-1 as well. The RNA binding properties of PABP-1 and PABP-4 appear to be identical []. Polyadenylate-binding protein 5 (PABP-5 or PABPC5):PABP-5 is encoded by PABPC5 gene within the X-specific subinterval, and expressed in fetal brain and in a range of adult tissues in mammals, such as ovary and testis. It may play an important role in germ cell development [
]. Moreover, unlike other PABPs, PABP-5 contains only four RRMs, but lacks both the linker region and the CTD. Polyadenylate-binding protein 1-like (PABP-1-like or PABPC1L): orthologue of PABP-1.Polyadenylate-binding protein 1-like 2 (PABPC1L2 or RBM32): orthologue of PABP-1. Polyadenylate-binding protein 4-like (PABP-4-like or PABPC4L): orthologue of PABP-5. Polyadenylate-binding protein, cytoplasmic and nuclear (PABP or ACBP-67): PABP is a conserved poly(A) binding protein containing poly(A) tails that can be attached to the 3'-ends of mRNAs. The yeast PABP, also known as Pab1, and its homologues may play important roles in the initiation of translation and in mRNA decay [
]. Like vertebrate PABP-1, Pab1 contains four RRMs, a linker region, and a proline-rich CTD as well. The first two RRMs are mainly responsible for specific binding to poly(A). The proline-rich region may be involved in protein-protein interactions. The association of RRM2 of yeast Pab1 with eIF4G is a prerequisite for the poly(A) tail to stimulate the translation of mRNA in vitro []. Polyadenylate-binding protein Pes4 and Mip6.
This entry represents the RNA recognition motif 2 (RRM2) of type I poly(A)-binding proteins (PABPs).
Poly(A)-binding proteins (PABPs) are highly conserved proteins that bind to the poly(A) tail present at the 3' ends of most eukaryotic mRNAs [
]. These highly conserved proteins are found only in eukaryotes; single-celled eukaryotes each have a single PABP, whereas humans have five and Arabidopis has eight. In humans, three lineages of PABP proteins are observed: cytoplasmic PABPs (PABPC1, PABPC3, and iPABP); nuclear PABP (PABPN1); and X-linked PABP (PABPC5) []. The mammalian PABPs contain four RNA recognition motifs (RRMs). RRM 1 and 2 are primarily responsible for the high-affinity binding to homopolymeric adenosines, while RRMs 3 and 4 can bind to nonhomopolymeric AU sequences []. Proteins containing this motif include:Polyadenylate-binding protein 1 (PABP-1 or PABPC1): PABP-1 is the major cytoplasmic PABP isoform in adult mouse somatic cells. It is able to bind
simultaneously to the cap-binding complex subunit eIF4G and to the poly(A) tail. Therefore, it has been suggested to play a role in altering the structure and/or function of the translation termination complex. It may have additional functions within the eukaryotic mRNA transcriptome. PABP-1 possesses an A-rich sequence in its 5'-UTR and allows binding of PABP and blockage of translation of its own mRNA []. Polyadenylate-binding protein 3 (PABP-3 or PABPC3): PABP-3 is a testis-specific poly(A)-binding protein specifically expressed in round spermatids. It is mainly found in mammalian and may play an important role in the testis-specific regulation of mRNA homeostasis. PABP-3 shows significant sequence similarity to PABP-1. However, it binds to poly(A) with a lower affinity than PABP-1. Dislike PABP-1, PABP-3 lacks the A-rich sequence in its 5'-UTR [
]. Polyadenylate-binding protein 4 (PABP-4 or APP-1 or iPABP): PABP-4 is an inducible poly(A)-binding protein (iPABP) that is primarily localized to the cytoplasm.
It shows significant sequence similarity to PABP-1 as well. The RNA binding properties of PABP-1 and PABP-4 appear to be identical []. Polyadenylate-binding protein 5 (PABP-5 or PABPC5):PABP-5 is encoded by PABPC5 gene within the X-specific subinterval, and expressed in fetal brain and in a range of adult tissues in mammals, such as ovary and testis. It may play an important role in germ cell development []. Moreover, unlike other PABPs, PABP-5 contains only four RRMs, but lacks both the linker region and the CTD. Polyadenylate-binding protein 1-like (PABP-1-like or PABPC1L): orthologue of PABP-1.Polyadenylate-binding protein 1-like 2 (PABPC1L2 or RBM32): orthologue of PABP-1. Polyadenylate-binding protein 4-like (PABP-4-like or PABPC4L): orthologue of PABP-5. Polyadenylate-binding protein, cytoplasmic and nuclear (PABP or ACBP-67): PABP is a conserved poly(A) binding protein containing poly(A) tails that can be attached to the 3'-ends of mRNAs. The yeast PABP, also known as Pab1, and its homologues may play important roles in the initiation of translation and in mRNA decay [
]. Like vertebrate PABP-1, Pab1 contains four RRMs, a linker region, and a proline-rich CTD as well. The first two RRMs are mainly responsible for specific binding to poly(A). The proline-rich region may be involved in protein-protein interactions. The association of RRM2 of yeast Pab1 with eIF4G is a prerequisite for the poly(A) tail to stimulate the translation of mRNA in vitro []. Polyadenylate-binding protein Pes4 and Mip6.
Thaumatin [
] is an intensely sweet-tasting protein, 100 000 times sweeter than sucrose on a molar basis [], found in berries from Thaumatococcus daniellii, a tropical flowering plant known as Katemfe. It is induced by attack by viroids, which are single-stranded unencapsulated RNA molecules that do not code for protein.Thaumatin consists of about 200 residues and contains 8 disulphide bonds. Like other PR proteins, thaumatin is predicted to have a mainly beta structure, with a high content of β-turns and little helix []. Several stress-induced proteins of plants have been found to be related to thaumatins:A maize alpha-amylase/trypsin inhibitorTwo tobacco pathogenesis-related proteins: PR-R major and minor forms, which are induced after infection with virusesSalt-induced protein NP24 from tomatoOsmotin, a salt-induced protein from tobacco [
]
Osmotin-like proteins OSML13, OSML15 and OSML81 from potato [
]
P21, a leaf protein from soybeanPWIR2, a leaf protein from wheat [
]
Zeamatin, a maize antifungal protein [
]
This family is also referred to as pathogenesis-related group 5 (PR5), as many thaumatin-like proteins accumulate in plants in response to infection by a pathogen and possess antifungal activity [
]. The proteins are involved in systemically acquired resistance and stress response in plants, although their precise role is unknown []. The PR5K receptor protein kinase from Arabidopsis comprises an extracellular domain related to the PR5 proteins, and an intracellular protein-serine/threonine kinase domain [].
This entry represents the Rdx family of selenoproteins, which includes mammalian selenoproteins SelW, SelV, SelT and SelH, bacterial SelW-like proteins and cysteine-containing proteins of unknown function in all three domains of life. Mammalian Rdx12 and its fish selenoprotein orthologues are also members of this family [
]. These proteins possess a thioredoxin-like fold and a conserved CXXC or CxxU (U is selenocysteine) motif near the N terminus, suggesting a redox function. Rdx proteins can use catalytic cysteine (or selenocysteine) to form transient mixed disulphides with substrate proteins. Selenium (Se) plays an essential role in cell survival and most of the effects of Se are probably mediated by selenoproteins. Selenoprotein W (SelW) plays an important role in protection of neurons from oxidative stress during neuronal development [
], []. Selenoprotein T (SelT) is conserved from plants to humans. SelT is localized to the endoplasmic reticulum through a hydrophobic domain. The protein binds to UDP-glucose:glycoprotein glucosyltransferase (UGTR), the endoplasmic reticulum (ER)-resident protein, which is known to be involved in the quality control of protein folding [
,
]. The function of SelT is unknown, although it may have a role in PACAP signaling during PC12 cell differentiation [,
]. Selenoprotein H (SelH) protects neurons against UVB-induced damage by inhibiting apoptotic cell death pathways, by preventing mitochondrial depolarization, and by promoting cell survival pathways [
].
Thioredoxins [
,
,
,
] are small disulphide-containing redox proteins that have been found in all the kingdoms of living organisms. Thioredoxin serves as a general protein disulphide oxidoreductase. It interacts with a broad range of proteins by a redox mechanism based on reversible oxidation of two cysteine thiol groups to a disulphide, accompanied by the transfer of two electrons and two protons. The net result is the covalent interconversion of a disulphide and a dithiol. In the NADPH-dependent protein disulphide reduction, thioredoxin reductase (TR) catalyses the reduction of oxidised thioredoxin (trx) by NADPH using FAD and its redox-active disulphide; reduced thioredoxin then directly reduces the disulphide in the substrate protein [].Thioredoxin is present in prokaryotes and eukaryotes and the sequence around the redox-active disulphide bond is well conserved. All thioredoxins contain a cis-proline located in a loop preceding β-strand 4, which makes contact with the active site cysteines, and is important for stability and function []. Thioredoxin belongs to a structural family that includes glutaredoxin, glutathione peroxidase, bacterial protein disulphide isomerase DsbA, and the N-terminal domain of glutathione transferase []. Thioredoxins have a beta-alpha unit preceding the motif common to all these proteins.A number of eukaryotic proteins contain domains evolutionary related to thioredoxin, most of them are protein disulphide isomerases (PDI). PDI (
) [
,
,
] is an endoplasmic reticulum multi-functional enzyme that catalyses the formation and rearrangement of disulphide bonds during protein folding []. All PDI contains two or three (ERp72) copies of the thioredoxin domain, each of which contributes to disulphide isomerase activity, but which are functionally non-equivalent []. Moreover, PDI exhibits chaperone-like activity towards proteins that contain no disulphide bonds, i.e. behaving independently of its disulphide isomerase activity []. The various forms of PDI which are currently known are:PDI major isozyme; a multifunctional protein that also function as the beta subunit of prolyl 4-hydroxylase (
), as a component of oligosaccharyl transferase (
), as thyroxine deiodinase (
), as glutathione-insulin transhydrogenase (
) and as a thyroid hormone-binding protein
ERp60 (ER-60; 58 Kd microsomal protein). ERp60 was originally thought to be a phosphoinositide-specific phospholipase C isozyme and later to be a protease.ERp72.ERp5.Bacterial proteins that act as thiol:disulphide interchange proteins that allows disulphide bond formation in some periplasmic proteins also contain a thioredoxin domain. These proteins include:Escherichia coli DsbA (or PrfA) and its orthologs in Vibrio cholerae (TtcpG) and Haemophilus influenzae (Por).E. coli DsbC (or XpRA) and its orthologues in Erwinia chrysanthemi and H. influenzae.E. coli DsbD (or DipZ) and its H. influenzae orthologue.E. coli DsbE (or CcmG) and orthologues in H. influenzae.Rhodobacter capsulatus (Rhodopseudomonas capsulata) (HelX), Rhiziobiacae (CycY and TlpA).This entry represents the thioredoxin protein family.
This entry represents Pentaxins and its related proteins such as CRP (C-reactive protein) and SAP (serum amyloid P component protein) [
]. This entry also includes adhesion G-protein coupled receptors D2 and G6 from humans.Pentraxins (or pentaxins) [
,
] are a family of proteins which show, under electron microscopy, a discoid arrangement of five noncovalently bound subunits. Proteins of the pentraxin family are involved in acute immunological responses []. Three of the principal members of the pentraxin family are serum proteins and Ca2 dependent: namely, C-reactive protein (CRP) [
], serum amyloid P component protein (SAP) [], and female protein (FP) []. CRP binds to ligands containing phosphocholine, SAP binds to amyloid fibrils, DNA, chromatin, fibronectin, C4-binding proteins and glycosaminoglycans.CRP is expressed during acute phase response to tissue injury or inflammation in mammals. The protein resembles antibody and performs several functions associated with host defence: it promotes agglutination, bacterial capsular swelling and phagocytosis, and activates the classical complement pathway through its calcium-dependent binding to phosphocholine. CRPs have also been sequenced in an invertebrate, Limulus polyphemus (Atlantic horseshoe crab), where they are a normal constituent of the hemolymph [
].SAP is a vertebrate protein that is a precursor of amyloid component P. It is found in all types of amyloid deposits, in glomerular basement menbrane and in elastic fibres in blood vessels. SAP binds to various lipoprotein ligands in a calcium-dependent manner, and it has been suggested that, in mammals, this may have important implications in atherosclerosis and amyloidosis [
].FP is a SAP homologue found in Mesocricetus auratus (golden hamster). The concentration of this plasma protein is altered by sex steroids and stimuli that elicit an acute phase response."Long"pentraxins have N-terminal extensions to the common pentraxin domain [
]; one group, the neuronal pentraxins, may be involved in synapse formation and remodeling, and they may also be able to form heteromultimers []. Pentraxin proteins expressed in the nervous system are neural pentraxin I (NPI) and II (NPII) []. NPI and NPII are homologous and can exist within one species. It is suggested that both proteins mediate the uptake of synaptic macromolecules and play a role in synaptic plasticity. Apexin, a sperm acrosomal protein, is a homologue of NPII found in Cavia porcellus (Guinea pig) [].PTX3 is a long pentraxin that provides defence against infectious agents and plays several functions in tissue repair and regulation of cancer-related inflammation [
].
Sad1/UNC-84 (SUN)-domain proteins are inner nuclear membrane (INM) proteins that are part of bridging complexes linking cytoskeletal elements with the nucleoskeleton. Originally identified based on an ~150-amino acid region of homology between the C terminus of the Schizosaccharomyces pombe Sad1 protein and the Caenorhabditis elegans UNC-84 protein, SUN proteins are present in the proteomes of most eucaryotes. In addition to the SUN domain, these proteins contain a transmembrane sequence and at least one coiled-coil domain and localise to the inner nuclear envelope. SUN proteins are anchored in the inner nuclear envelope by their transmembrane segment and oriented in the membrane such that the C-terminal SUN domain is located in the space between the inner and outer nuclear membrane. Here, the SUN domain can interact with the C- terminal tail of an outer nuclear envelope protein that binds to the cytoskeleton, including the centrosome [
,
,
].Some proteins known to contain a SUN domain are listed below:Fission yeast spindle pole body-associated protein Sad1.Yeast spindle pole body assembly component MPS3, essential for nuclear division and fusion.Yeast uncharacterised protein SLP1.Caenorhabditis nuclear migration and anchoring protein UNC-84.Caenorhabditis SUN domain-containing protein 1 (sun-1), involved in centrosome attachment to the nucleus.Mammalian sperm-associated antigen 4 protein (SPAG4), may assist the organisation and assembly of outer dense fibres (ODFs), a specific structure of the sperm tail.Mammalian sperm-associated antigen 4-like protein (SPAG4L).Mammalian SUN1.Mammalian SUN2.Mammalian SUN3.Klaroid protein from Drosophila melanogaster [
].
FCH domain is a short conserved region of around 60 amino acids first described as a region of homology between FER and CIP4 proteins [
]. In the CIP4 protein the FCH domain binds to microtubules []. The FCH domain is always found N-terminally and is followed by a coiled-coil region. The FCH and coiled-coil domains are structurally similar to Bin/amphiphysin/RVS (BAR) domains []. They are α-helical membrane-binding modules that function in endocytosis, regulation of the actin cytoskeleton and signalling []. Proteins containing an FCH domain can be divided in 3 classes [
]:A subfamily of protein kinases usually associated with an SH2 domain:Fps/fes (Fujimani poultry sarcoma/feline sarcoma) proto-oncogenes. They are non-receptor protein-tyrosine kinases preferentially expressed in myeloid lineage. The viral oncogene has an unregulated kinase activity which abrogates the need for cytokines and influences differentiation of haematopoietic progenitor cells.Fes related protein (fer). It is an ubiquitously expressed homologue of Fes.Adaptor proteins usually associated with a C-terminal SH3 domain:Schizosaccharomyces pombe CDC15 protein. It mediates cytoskeletal rearrangements required for cytokinesis. It is essential for viability.CD2 cytoplasmic domain binding protein.Mammalian Cdc42-interacting protein 4 (CIP4). It may act as a link between Cdc42 signaling and regulation of the actin cytoskeleton.Mammalian PACSIN proteins. A family of cytoplasmic phosphoproteins playing a role in vesicle formation and transport.A subfamily of Rho-GAP proteins:Mammalian RhoGAP4 proteins. They may down-regulate Rho-like GTPases in hematopoietic cells.Yeast RHO GTPase-activating protein RGD1 (also known as YBR260C).Caenorhabditis elegans hypothetical protein ZK669.1.
