Guanosine cyclase 3',5'-dependent protein kinases are known to play a role in smooth muscle relaxation, ion fluxes in kidneys and intestines, and neuronal function. The predominant form of cGMP-dependent protein kinase is a dimer of identical 75kDa subunits, although larger subunits of 86 and 130kDa have been found [
]. The enzyme is kept in an inactive form by the interaction of the catalytic domain of one subunit with the region on the other subunit that precedes the cGMP binding domain. Each subunit contains two cGMP-binding regions, found together in the sequence: binding of two molecules of cGMP precipitates a conformational change in the active site that allows the substrate to bind.Although cGMP- and cAMP-dependent protein kinases are similar both in structure and sequence around the nucleotide binding site, and in the method of activation and inactivation, there are some basic contrasts. The major difference is that all of the functional domains of the cGMP- dependent enzymes are found on a single polypeptide chain, whereas cAMP-dependent protein kinases have separate regulatory (cAMP binding) and catalytic chains.
Ras-related protein Rab9 is a member of the large Rab GTPase family. It is found in late endosomes, together with mannose 6-phosphate receptors (MPRs) and the tail-interacting protein of 47kDa (TIP47). Rab9 is a key mediator of vesicular transport from late endosomes to the trans-Golgi network (TGN) by redirecting the MPRs [
]. Rab9 has been identified as a key component for the replication of several viruses, including HIV1, Ebola, Marburg, and measles, making it a potential target for inhibiting a variety of viruses [].Rabs are regulated by GTPase activating proteins (GAPs), which interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins [,
].
MORF4 (mortality factor on chromosome 4), MRG15 (MORF4-related gene on chromosome 15) and MRGX (MORF4-related gene on chromosome X) are members of the MRG protein family that were first identified as transcription factors involved in cellular senescence. All expressed members of the MRG family are localized to the nucleus and have predicted motifs that indicate they function as chromatin remodeling complex components. MORF4, MRG15 and MRGX share a common C-terminal part but a different N-terminal part. The C-terminal similarity of all MRG family members (MORF4, MRG15 and MRGX homologues) defines a new conserved protein domain. The ~170 amino acid MRG domain binds a plethora of transcriptional regulators and chromatin-remodeling factors, including the histone deacetylase transcriptional corepressor mSin3A and the nuclear protein PAM14 (protein-associated MRG, 14kDa) [
,
].The MRG domain consists of three conserved blocks. It is predominantly hydrophobic, and consists of mainly α-helices that are arranged in a three layer sandwich topology. The hydrophobic core is stabilised by interactions among a number of conserved hydrophobic residues. The molecular surface is largely hydrophobic, but contains a few hydrophilic patches [
,
,
].
Cellulose, an aggregate of unbranched polymers of beta-1,4-linked glucose residues, is the major component of wood and thus paper, and is synthesized by plants, most algae, some bacteria and fungi, and even some animals. The genes that synthesize cellulose in higher plants differ greatly from the well-characterised genes found in Acetobacter and Agrobacterium spp. More correctly designated as "cellulose synthase catalytic subunits", plant cellulose synthase (CesA) proteins are integral membrane proteins, approximately 1,000 amino acids in length. There are a number of highly conserved residues, including several motifs shown to be necessary for processive glycosyltransferase activity [
].An operon encoding 4 proteins required for bacterial cellulose biosynthesis
(bcs) in Acetobacter xylinus (Gluconacetobacter xylinus) has been isolated via genetic complementationwith strains lacking cellulose synthase activity [
]. Nucleotide sequence analysis showed the cellulose synthase operon to consist of 4 genes, designated bcsA, bcsB, bcsC and bcsD, all of which are required for maximal bacterial cellulose synthesis in A. xylinum.
The calculated molecular mass of the protein encoded by bcsD is 17.3kDa [
]. The function of BcsD is unknown.
Gelsolin is a cytoplasmic, calcium-regulated, actin-modulating protein that binds to the barbed ends of actin filaments, preventing monomer exchange (end-blocking or capping) [
]. It can promote nucleation (the assembly of monomers into filaments), as well as sever existing filaments. In addition, this protein binds with high affinity to fibronectin. Plasma gelsolin and cytoplasmic gelsolin are derived from a single gene by alternate initiation sites and differential splicing.Sequence comparisons indicate an evolutionary relationship between gelsolin,
villin, fragmin and severin []. Six large repeating segments occur in gelsolin and villin, and 3 similar segments in severin and fragmin. While the multiple repeats have yet to be related to any known function of the actin-severing proteins, the superfamily appears to have evolved from an ancestral sequence of 120 to 130 amino acid residues [].This gelsolin-like domain can also be found in the C-terminal of the members of Sec23/Sec24 family. They are components of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The Gelsolin structure has a three layers (α/β/α) fold and a mixed β-sheet topology.
Glutathione (GSH), the major low-molecular-weight thiol compound in most eukaryotic cells, is normally degraded through the gamma-glutamyl cycle initiated by the action of gamma-glutamyl transpeptidase. A novel pathway for the degradation of GSH that requires the participation of three previously uncharacterised genes has been identified in Saccharomyces cerevisiae. These genes are Dug1 (YFR044c), Dug2 (YBR281c), and Dug3 (YNL191w), which is defective in utilization of glutathione. Although dipeptides and tripeptides with a normal peptide bond, such as cys-gly or glu-cys-gly, can be hydrolysed by the Dug1 protein (a metallopeptidase), the presence of an unusual peptide bond, such as in GSH, requires the participation of the Dug2 and Dug3 gene products as well. The Dug3 gene encodes a protein with a glutamine amidotransferase domain. These three proteins form a GSH degradosomal complex [
]. This entry represents DUG2, which encodes a protein with a metallopeptidase domain and a large WD40 repeat region. However, it has no peptidase activity. Dug2 form a complex with Dug3. The (Dug2-Dug3)2 complex functions as a glutamine amidotransferase (GATase) enzyme acting on glutathione [
].
Hemopexin (
) is a serum glycoprotein that binds haem and transports it to the liver for breakdown and iron recovery, after which the free hemopexin returns to the circulation [
]. Hemopexin prevents haem-mediated oxidative stress. Structurally hemopexin consists of two similar halves of approximately two hundred amino acid residues connected by a histidine-rich hinge region. Each half is itself formed by the repetition of a basic unit of some 35 to 45 residues. Hemopexin-like domains have been found in two other types of proteins, vitronectin [], a cell adhesion and spreading factor found in plasma and tissues, and matrixins MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, MMP-11, MMP-12, MMP-14, MMP-15 and MMP-16, members of the matrix metalloproteinase family that cleave extracellular matrix constituents []. These zinc endopeptidases, which belong to MEROPS peptidase subfamily M10A, have a single hemopexin-like domain in their C-terminal section. It is suggested that the hemopexin domain facilitates binding to a variety of molecules and proteins, for example the HX repeats of some matrixins bind tissue inhibitor of metallopeptidases (TIMPs).
NfeD-like proteins are widely distributed throughout prokaryotes and are frequently associated with genes encoding stomatin-like proteins (slipins) [
]. The homologue from hyperthermophilic archaebacterium Pyrococcus horikoshii is thought to be a serine protease involved in ion channel opening through the cleavage of a stomatin-homologue [].There appear to be three major groups of NfeD-like proteins: an ancestral group with only an N-terminal serine protease domain and this C-terminal beta sheet-rich domain which is structurally very similar to the OB-fold domain [
], associated with its neighbouring slipin cluster; a second major group with an additional middle, membrane-spanning domain, associated in some species with eoslipin and in others with yqfA; a final 'artificial' group which unites truncated forms lacking the protease region and associated with their ancestral gene partner, either yqfA or eoslipin.This NefD, C-terminal domain appears to be the major one for relating to the associated protein. NfeD homologues are clearly reliant on their conserved gene neighbour which is assumed to be necessary for function, either through direct physical interaction or by functioning in the same pathway, possibly involve with lipid-rafts [
].
This entry represents the RNA recognition motif 1 (RRM1) of IGF2BP2.Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2, also known as IMP-2) is a ubiquitously expressed RNA-binding protein that recruits target transcripts to cytoplasmic protein-RNA complexes (mRNPs) [
]. It is involved in the stimulation of insulin action and has a role in metabolic homeostasis []. SNPs in IGF2BP2 gene are implicated in susceptibility to type 2 diabetes []. IGF2BP2 also plays an important role in cellular motility; it regulates the expression of PINCH-2, an important mediator of cell adhesion and motility, and MURF-3, a microtubule-stabilizing protein, through direct binding to their mRNAs []. IGF2BP2 may be involved in the regulation of mRNA stability through the interaction with the AU-rich element-binding factor AUF1 []. IGF2BP2 belongs to the IGF2BP family, which includes IGF2BP1, IGF2BP2, and IGF2BP3. They have different functions, such as cell polarisation, migration, morphology, metabolism, proliferation and differentiation [
]. They contain four hnRNP K-homology (KH) domains, two RNA recognition motifs (RRMs) and a RGG RNA-binding domain.
Alpha-lactalbumin comprises 15 percent of the total human milk protein and is essential for lactose production [
]. It is a globular calcium-binding metalloprotein secreted in the lactating mammary gland [], the calcium being bound in a novel binding loop that is superficially similar to the classic EF-hand motif. Lactalbumin attaches to beta-galactosyltransferase on the luminal surface of the Golgi apparatus, creating the lactose synthetase complex [], which catalyses the addition of galactose to glucose, forming lactose. It has been claimed that calcium controls the release of lactalbumin from the golgi membrane and that the pattern of ion binding may also affect the catalytic properties of the lactose synthetase complex. The lactalbumin gene also contains a novel upstream regulatory sequence called the `milk box' [], which is also found in genes of other milk proteins, and may be involved in either hormone regulation or tissue-specific expression in the lactating mammary gland.Alpha-lactalbumin is similar to C-type lysozyme in terms of primary sequence and structure [
], and has probably evolved from a common ancestral protein. There is, however, no similarity in function.
Interleukin-1 receptor-associated kinase 1, death domain
Type:
Domain
Description:
Interleukin-1 receptor-associated kinases (IRAKs) are essential components of innate immunity and inflammation in mammals and other vertebrates. They are involved in signal transduction pathways involving IL-1 and IL-18 receptors, Toll-like receptors, nuclear factor-kappaB (NF-kB), and mitogen-activated protein kinases (MAPKs). IRAKs contain an N-terminal death domain (DD) and a C-terminal kinase domain [
,
,
,
].IRAK1 is an active kinase and also plays adaptor functions. It binds to the MyD88-IRAK4 complex via its DD, which facilitates its phosphorylation by IRAK4, activating it for further auto-phosphorylation [
]. Hyper-phosphorylated IRAK1 forms a cytosolic complex with TRAF6, leading to the activation of NF-kB and MAPK pathways. IRAK1 is involved in autoimmunity and may be associated with lupus pathogenesis [].Death domains (DDs) are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes [
].
STKs (serine/threonine-protein kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. RSK3 (also known as RPS6KA2) is one of four RSK isoforms (RSK1-4) from distinct genes present in vertebrates. RSK3 binds muscle A-kinase anchoring protein (mAKAP)-b directly and regulates concentric cardiac myocyte growth [
]. The RSK3 gene, RPS6KA2, is a putative tumour suppressor gene in sporadic epithelial ovarian cancer and variations to the gene may be associated with rectal cancer risk [].RSKs (90kDa ribosomal S6 kinases) contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family. They are activated by signalling inputs from extracellular regulated kinase (ERK) and phosphoinositide dependent kinase 1 (PDK1). ERK phosphorylates and activates the CTD of RSK, serving as a docking site for PDK1, which phosphorylates and activates the NTD, which in turn phosphorylates all known RSK substrates. RSKs act as downstream effectors of mitogen-activated protein kinase (MAPK) and play key roles in mitogen-activated cell growth, differentiation, and survival [
,
,
].
Antifreeze proteins (AFPs) are defined by their ability to bind ice and prevent it from growing. In this way they function in both freeze-resistance and freeze-tolerance strategies of organisms that live at sub-zero temperatures and require protection from ice growth. In fish, five AFP types have been described that are remarkably diverse in their 3D structures. They have completely dissimilar folds and no sequence homology. Type III AFPs found in eelpouts are 65-residue proteins with a compact globular fold formed from short β-strands, which presents a flat ice binding surface. These proteins are homologous to the C-terminal region of mammalian and prokaryotic sialic acid synthase (SAS; gene neuB), which has been called AFP-like domain [
]. The similarity is greatest in the protein core and the flat ice-binding region. SAS is involved in the condensation of phosphoenolpyruvate with N-acetylmannosamine derivatives to generate N-acetylneuraminic acid, an intermediate used for the sialylation of glycoconjugates. The function of the AFP-like domain, which is a β-clip fold [], in SAS is not known, but it has been proposed that it could be involved in sugar binding.
This entry represents the ankyrin repeat-containing domain. These domains contain multiple repeats of a β(2)-α(2) motif. The ankyrin repeat is one of the most common protein-protein interaction motifs in nature. Ankyrin repeats are tandemly repeated modules of about 33 amino acids. They occur in a large number of functionally diverse proteins mainly from eukaryotes. The few known examples from prokaryotes and viruses may be the result of horizontal gene transfers [
]. The repeat has been found in proteins of diverse function such as transcriptional initiators, cell-cycle regulators, cytoskeletal, ion transporters and signal transducers. The ankyrin fold appears to be defined by its structure rather than its function since there is no specific sequence or structure which is universally recognised by it. The conserved fold of the ankyrin repeat unit is known from several crystal and solution structures [
,
,
,
]. Each repeat folds into a helix-loop-helix structure with a β-hairpin/loop region projecting out from the helices at a 90oangle. The repeats stack together to form an L-shaped structure [
,
].
This entry represents all three varieties (Fe-Fe, Mo-Fe and V-Fe) of the component I alpha chain of nitrogenase.Nitrogenase (
) [
] is the enzyme system responsible for biological nitrogen fixation. Nitrogenase is an oligomeric complex which consists of two components: component 2 is an homodimer of an iron-sulphur protein, while component 1 which contains the active site for the reduction of nitrogen to ammonia exists in three different forms: the molybdenum-iron containing protein (MoFe) is a hetero-tetramer consisting of two pairs of alpha (nifD) and beta (nifK) subunits; the vanadium-iron containing protein (VFe) is a hexamer of two pairs each of alpha (vnfD), beta (vnfK), and delta (vnfG) subunits; the third form seems to only contain iron and is a hexamer composed of alpha (anfD), beta (anfK), and delta (anfG) subunits.The alpha and beta chains of the three types of component 1 are evolutionary related and they are also related to proteins nifE and nifN, which are most probably involved in the iron-molybdenum cofactor biosynthesis [
].
This entry includes the family M35 Zn
2+-metallopeptidase extracellular domain from proteins characterized as peptidyl-Lys metalloendopeptidases (MEP; peptidyllysine metalloproteinase; EC 3.4.24.20; MEROPS identifier M35.004), including some well-characterized domains in Armillaria mellea [
], Aeromonas salmonicida subsp. achromogenes (AsaP1) [,
] and Grifola frondosa (GfMEP) [,
,
]. These proteins specifically cleave peptidyl-lysine bonds (-X-Lys- where X may even be Pro) in proteins and peptides. AsaP1 peptidase (MEROPS identifier M35.003) has been shown to be important in the virulence of A. salmonicida subsp. achromogenes, having a major role in the fish innate immune response []. AsaP1 is synthesized as an inactive precursor, the structure of which shows that the propeptide inhibits activity by inserting a lysine into the S1' pocket of active site [].Peptidase family M35 contains metalloendopeptidases known as Asp-zincins, in which a single catalytic zinc ion is ligated by two histidines in an HExxH motif and an aspartic acid in a GTXDXXYG or similar motif C-terminal to the HExxH motif. The glutamic acid in the HExxH motif is a catalytic residue [
].
Many microorganisms, such as methanogenic, acetogenic, nitrogen-fixing, photosynthetic, or sulphate-reducing bacteria, metabolise hydrogen. Hydrogen activation is mediated by a family of enzymes, termed hydrogenases, which either provide these organisms with reducing power from hydrogen oxidation, or act as electron sinks. There are two hydrogenases families that differ functionally from each other: NiFe hydrogenases tend to be more involved in hydrogen oxidation, while Iron-only FeFe (Fe only) hydrogenases in hydrogen production. Fe only hydrogenases (
) can either be monomeric and cytoplasmic or heterodimeric and periplasmic, being involved in either hydrogen production or uptake, respectively. This entry represents the small subunit of the heterodimeric enzyme, which is comprised of alternating random coil and alpha helical structures that encompass the large subunit in a novel protein fold [
].A domain homologous to the small subunit is found at the C terminus of iron-only hydrogenase-like protein 1 (IOP1) and IOP2 (also known as nuclear prelamin A recognition factor), two orthologue proteins found in mammalian cells. IOP1 has been shown to be involved in mammalian cytosolic Fe-S protein maturation [
].
This entry includes the catalytic domain of the protein ImmA (MEROPS identifier M78.001), which is a metallopeptidase containing an HEXXH zinc-binding motif. ImmA is encoded on a conjugative transposon. Conjugating bacteria are able to transfer conjugative transposons that can, for example, confer resistance to antibiotics. The transposon is integrated into the chromosome, but during conjugation excises itself and then moves to the recipient bacterium and re-integrate into its chromosome. Typically a conjugative tranposon enodes only the proteins required for this activity and the proteins that regulate it. During exponential growth, the ICEBs1 transposon of Bacillus subtilis is inactivated by the immunity repressor protein ImmR, which is encoded by the transposon and represses the genes for excision and transfer. Cleavage of ImmR relaxes repression and allows transfer of the transposon. ImmA has been shown to be essential for the cleavage of ImmR [
].This domain is also found in in metalloprotease IrrE, a central regulator of DNA damage repair in Deinococcaceae [
], HTH-type transcriptional regulators RamB [] and PrpC [].
CBS domains are evolutionarily conserved structural domains found in a variety of non functionally-related proteins from all kingdoms of life. These domains pair together to form a intramolecular dimeric structure (CBS pair), termed Bateman domain [
,
,
,
]. CBS domains have been shown to bind mainly ligands with an adenosyl group such as AMP, ATP and S-AdoMet, but may also bind metal ions, or nucleic acids [,
]. Hence, they play an essential role in the regulation of the activities of numerous proteins, and mutations in them are associated with several hereditary diseases [,
,
]. CBS domains are found attached to a wide range of other protein domains suggesting that CBS domains may play a regulatory role making proteins sensitive to adenosyl-carrying ligands. The region containing the CBS domains in cystathionine-beta synthase is involved in regulation by S-AdoMet []. CBS domain pairs from AMPK bind AMP or ATP []. The CBS domains from IMPDH, which bind ATP, have shown to have a role in the regulation of adenylate nucleotide synthesis [,
].
Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium,
nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds [
,
,
]. The metallothionein superfamily comprises all polypeptides that resemble equine renal metallothionein in several respects, e.g. low molecular
weight; high metal content; amino acid composition with high Cys and low aromatic residue content; unique sequence with characteristic distribution of cysteines, and spectroscopic manifestations
indicative of metal thiolate clusters. A MT family subsumes MTs that share particular sequence-specific features and are thought to be evolutionarily related. Fifteen MT families have been characterised,
each family being identified by its number and its taxonomic range.Fungi-IV (family 11) MTs are
proteins of about 55-56 residues, with 9 conserved cysteines. Its members are recognised by the sequence pattern C-X-K-C-x-C-x(2)-C-K-C. The taxonomic range of the members extends to ascomycotina.
The protein contains a number of unusual histidine and phenylalanine residues conserved in the N-terminal part of the sequence. This fragment does not contain any Cys. The protein binds to copper ions.
Phasins (or granule-associate proteins) are surface proteins found covering Polyhydroxyalkanoate (PHA) storage granules in bacteria. Polyhydroxyalkanoates are linear polyesters produced by bacterial fermentation of sugar or lipids for the purpose of storing carbon and energy, and are accumulated as intracellular granules by many bacteria under unfavorable conditions, enhancing their fitness and stress resistance [
]. The layer of phasins stabilises the granules and prevents coalescence of separated granules in the cytoplasm and nonspecific binding of other proteins to the hydrophobic surfaces of the granules. For example, in Ralstonia eutropha (strain ATCC 17699/H16/DSM 428/Stanier 337) (Cupriavidus necator (strain ATCC 17699 / H16 / DSM 428 / Stanier 337)), the major surface protein of polyhydroxybutyrate (PHB) granules is phasin PhaP1(Reu), which occurs along with three homologues (PhaP2, PhaP3, and PhaP4) that have the capacity to bind to PHB granules but are present at minor levels [,
]. These four phasins lack a highly conserved domain but share homologous hydrophobic regions. This entry represents a family of phasins that are part of the polyhydroxyalkanoate synthesis machinery [
]. Members of this family are related to .
Connector enhancer of kinase suppressor of ras 2/3 domain
Type:
Domain
Description:
This region is found in Connector enhancer of kinase suppressor of ras 2 (CNK2), Connector enhancer of kinase suppressor of ras 3 (CNK3) and CNK3/IPCEF1 fusion protein. This domain of unknown function is situated between the PDZ
and PH
domains in CNK2 and CNK3/IPCEF1 proteins and after the PDZ domain in CNK3 (which does not have a PH domain). CNK2 is predominantly expressed in neural tissues, being critical for postsynaptic density morphology, implicated in X-linked intellectual disability (ID). CNK2 was first described as a regulator of Ras/MAPK signalling by binding to the Ras effector RAF that lead to further studies concluding that it act as a scaffold for multiple signal cascades. It is able to direct the localisation of regulatory proteins within the cell and influences the behaviour of important regulatory molecules [
,
]. CNK3 regulates aldosterone-induced and epithelial sodium channel (ENaC)-mediated sodium transport through regulation of ENaC cell surface expression, acting as a scaffold protein that coordinates the assembly of an ENaC-regulatory complex (ERC) []. CNK3/IPCEF1 is required for hepatocyte growth factor (HGF)-dependent activation of Arf6 and HGF-stimulated cell migration [].
The host selective cysteine rich necrotrophic effector Tox1(SnTox1) found in Parastagonospora nodorum is a necrotrophic effector that contains 6 cysteine residues, a common feature for some fungal avirulence effectors such as the Avr and ECP effectors from Cladosporium fulvum. The high content of cysteine residues and high stability suggest that SnTox1 may function in the plant apoplastic space which is abundant in plant defense components. Protein sequence analysis indicate that SnTox1 contains a C-terminal chitin binding (CB) like motif. Three-dimensional (3D) structure-based sequence alignment suggested that the putative CB motif in SnTox1 was more similar to those of plant-specific ChtBDs than to Avr4 proteins, which are related to invertebrate ChtBDs. Furthermore, SnTox1 contained all secondary-structure-related residues including the strictly conserved b-strand-forming 'CCS' motif found only in plant-specific ChtBD1 proteins [
,
]. It interacts with the host Snn1 protein conferring susceptibility. Binding of SnTox1 to chitin in the fungal cell wall protects the pathogen from chitinase activity.This entry represents the putative chiting binding-like domain found in SnTox1 from Parastagonospora nodorum.
This family includes a group of BAR-domain containing proteins, including BIN3 from human, its homologues RVS161 and hob3 from S. cerevisiae and S. pombe, respectively, and related proteins, which contain the N-BAR domain, related to the amphiphysin family of proteins [
,
]. BIN3 is widely expressed in many tissues except in the brain. It plays roles in regulating filamentous actin localization and in cell division [].This entry also includes reduced viability upon starvation protein 167 (RVS167) from S. cerevisiae and its homologue in S. pombe, hob1 [
,
,
]. RVS161/167 are components of a cytoskeletal structure that is required for the formation of endocytic vesicles at the plasma membrane level and form a complex that regulates actin, endocytosis, and viability following starvation or osmotic stress. Hob1 is structurally similar to RVS167, while hob3 is more similar to human BIN3 and RVS161, however, neither hob1 nor hob3 is required for endocytosis, []. Hob1 is dispensable for endocytosis, actin organization, or osmotic sensitivity but it participates in DNA damage signalling as a part of stress response processes.
This entry includes archaeal exosome complex component Csl4 and its homologues from eukaryotes. In budding yeast, Csl4 is also known as Ski4 due to its
superkiller (SKI) phenotype first described as a more efficient ability to kill sensitive non-killer yeast strains [,
]. Later, it was found to be part of the yeast exosome complex involved in 3'-5' RNA processing and degradation in both the nucleus and the cytoplasm [].Csl4 is a non-catalytic component of the exosome, a complex involved in RNA processing and degradation [
,
]. The exact composition of the exosome varies, depending on the organism or the subcellular localization, but in all cases it is composed of a ring-shaped core made of three heterodimers (Rrp41p/Rrp45p, Rrp43p /Rrp46p, Rrp42p/Mtr3p) stabilized by the presence of three other proteins (Csl4/Ski4, Rrp4p, Rrp40p) []. The presence of different proteins in the cap may enable interactions with different substrates. It has been shown that the archaeal DnaG protein needs Csl4 for binding to the exosome. DnaG is a poly(A)-binding protein and enhances the degradation of adenine-rich transcripts by the Csl4-exosome [].
Many Gram-negative pathogenic bacteria directly translocate effector proteins into eukaryotic host cells via a type III secretion system. Type III effector proteins are determinants of virulence on susceptible plant hosts; they are also the proteins that trigger specific disease resistance in resistant plant hosts. Evolution of type III effectors is dominated by competing forces: the likely requirement for conservation of virulence function, the avoidance of host defenses, and possible adaptation to new hosts. Members of this family of plant pathogenic proteins adopt an elongated structure somewhat reminiscent of a mushroom that can be divided into 'stalk' and 'head' subdomains. The stalk subdomain is composed of the N-terminal helix (alpha1) and beta strands beta3-beta4. An antiparallel beta sheet (beta5, beta7-beta8) forms the base of the head subdomain that interacts with the stalk. A pair of twisted antiparallel beta sheets (beta1 and beta6; beta2 and beta9/9') supported by alpha2 form the dome of the head. The head subdomain possesses weak structural similarity with the catalytic portion of a number of ADP-ribosylt ransferase toxins [
].
NF-kappa B proteins are part of a protein complex that acts as a transcription factor, which is responsible for regulating a host of cellular responses to a variety of stimuli. This complex tightly regulates the expression of a large number of genes, and is involved in processes such as adaptive and innate immunity, stress response, inflammation, cell adhesion, proliferation and apoptosis. The cytosolic NF-kappa B complex is activated via phosphorylation of the ankyrin-repeat containing inhibitory protein I-kappa B, which dissociates from the complex and exposes the nuclear localization signal of the heterodimer (NF-kappa B and Rel) [
,
]. c-Rel plays an important role in B cell proliferation and survival [].Proteins containing the Rel homology domain (RHD) are metazoan transcription factors. The RHD is composed of two structural sub-domains. This entry represents the N-terminal RHD sub-domain of the c-Rel family of transcription factors, categorized as a class II member of the NF-kappa B family. In class II NF-kappa Bs, the RHD domain co-occurs with a C-terminal transactivation domain (TAD) [
,
].
The Bacteriophage T4 gene 59 helicase assembly protein (Gp59) is required for recombination-dependent DNA replication and repair, which is the predominant mode of DNA replication in the late stage of T4 infection. Gp59 accelerates the loading of the T4 gene 41 helicase during DNA synthesis by the T4 replication system in vitro. This protein binds to both T4 gene 41 helicase and T4 gene 32 single-stranded DNA binding protein, and to single and double-stranded DNA [
].The C-terminal domain of the T4 gene 59 helicase assembly protein consists of seven α-helices with short intervening loops and turns; the surface of the domain contains large regions of exposed hydrophobic residues and clusters of acidic and basic residues. The hydrophobic region on the 'bottom' surface of the domain near the C-terminal helix binds the leading strand DNA, whilst the hydrophobic region on the, top, surface of the domain lies between the two arms of the fork DNA, allowing for T4 gene 41 helicase binding and assembly into a hexameric complex around the lagging strand [
].
Sorbin is an active peptide present in the digestive tract, where it has pro-absorptive and anti-secretory effects in different parts of the intestine, including the ability to decrease VIP (vasoactive intestinal peptide) and cholera toxin-induced secretion. It is expressed in some intestinal and pancreatic endocrine tumours in humans [
].Sorbin-homology (SoHo) domains are found in adaptor proteins such as vinexin, CAP/ponsin and argBP2, which regulate various cellular functions, including cell adhesion, cytoskeletal organisation, and growth factor signalling [
]. In addition to the sorbin domain, these proteins contain three SH3 (src homology 3) domains. The sorbin homology domain mediates the interaction of vinexin and CAP with flotillin, which is crucial for the localisation of SH3-binding proteins to the lipid raft, a region of the plasma membrane rich in cholesterol and sphingolipids that acts to concentrate certain signalling molecules. The sorbin homology domain of adaptor proteins may mediate interactions with the lipid raft that are crucial to intracellular communication [
].Human sorbin is generated via splicing of an alternative transcript from the ArgBP2 gene locus [
].
BRCA2 participates in homologous recombination-mediated repair of double-strand DNA breaks [
,
]. It stimulates the displacement of Replication protein A (RPA), the most abundant eukaryotic ssDNA binding protein []. Mutations that map throughout the BRCA2 protein are associated with breast cancer susceptibility []. BRCA2 is a large nuclear protein and its most conserved region is the C-terminal BRCA2DBD. BRCA2DBD binds ssDNA in vitro, and is composed of five structural domains, three of which are OB folds (OB1, OB2, and OB3). BRCA2DBD OB2 and OB3 are arranged in tandem, and their mode of binding can be considered qualitatively similar to two OB folds of RPA1, DBD-A and DBD-B (the major DBDs of RPA) []. This entry represents OB3, which consists of a highly curved five-stranded β-sheet that closes on itself to form a β-barrel. OB3 has a pronounced groove formed by one face of the curved sheet and is demarcated by two loops, one between β1 and β2 and another between β4 and β5, which allows for strong ssDNA binding [
].
Synonym(s): Paraoxonase, A-esterase, Aryltriphosphatase, Phosphotriesterase, Paraoxon hydrolase Bacteria such as Brevundimonas diminuta (Pseudomonas diminuta) harbour a plasmid that carries the gene for aryldialkylphosphatase (
) (PTE) (also known as parathion hydrolase). This enzyme has attracted interest because of its potential use in the detoxification of chemical waste and warfare agents and its ability to degrade agricultural pesticides such as parathion. It acts specifically on synthetic organophosphate triesters and phosphorofluoridates. It does not seem to have a naturally occuring substrate and may thus have optimally evolved for utilizing paraoxon.
Aryldialkylphosphatase belongs to a family [
,
] of enzymes that possess a binuclear zinc metal centre at their active site. The two zinc ions are coordinated by six different residues, six of which being histidines. This family so far includes, in addition to the parathion hydrolase, the following proteins:Escherichia coli protein Php, the substrate of which is not yet known.Mycobacterium tuberculosis phosphotriesterase homology protein Rv0230C.Mammalian phosphotriesterase related protein (PTER) (RPR-1).This entry corresponds to the region located in the N-terminal section that contains two histidines that bind the first of the two zinc ions.
This domain of about 70 amino acid residues is related to the Krueppel-associated box (KRAB) domain and has been recently stratified as the ancestral KRAB domain (aKRAB). Sequence analysis revealed that these sequences have a motif that can also be traced in invertebrates, whose homologues still exist in mammals, including humans, in the PR/SET domain 9 (PRDM9) and synovial sarcoma X breakpoint (SSX) orthologous and paralogous groups [
]. This domain is found in the N-terminal ends of PRDM9 and proteins belonging to the SSX family [,
,
]. Proteins of the SSX family lack the C2H2-type zinc finger which is invariably found in proteins containing the KRAB domain.Although the aKRAB domains of SSX1 and SSX2 contribute to the repressive activity of these proteins, transcriptional repression is mainly mediated by an auxiliary region located in their C terminus, called KRAB-B [
]. Hence, unlike the canonical KRAB domain, the aKRAB domain is only a weak transcriptional repression domain, as seen in human PRDM9, which neither silences transcription nor interacts with TRIM28/KAP1 [,
].
The Bacteriophage T4 gene 59 helicase assembly protein (Gp59) is required for recombination-dependent DNA replication and repair, which is the predominant mode of DNA replication in the late stage of T4 infection. Gp59 accelerates the loading of the T4 gene 41 helicase during DNA synthesis by the T4 replication system in vitro. This protein binds to both T4 gene 41 helicase and T4 gene 32 single-stranded DNA binding protein, and to single and double-stranded DNA [
].The C-terminal domain of the T4 gene 59 helicase assembly protein consists of seven α-helices with short intervening loops and turns; the surface of the domain contains large regions of exposed hydrophobic residues and clusters of acidic and basic residues. The hydrophobic region on the 'bottom' surface of the domain near the C-terminal helix binds the leading strand DNA, whilst the hydrophobic region on the, top, surface of the domain lies between the two arms of the fork DNA, allowing for T4 gene 41 helicase binding and assembly into a hexameric complex around the lagging strand [
].
Dynein is a multisubunit microtubule-dependent motor enzyme that acts as the force generating protein of eukaryotic cilia and flagella. The cytoplasmic isoform of dynein acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.Dynein is composed of a number of ATP-binding large subunits (see
), intermediate size subunits and small subunits. Among the small subunits, there is a family of highly conserved proteins which make up this family [
,
,
]. Proteins in this family act as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function and may play a role in changing or maintaining the spatial distribution of cytoskeletal structures. In yeast, it was identified as a component of the nuclear pore complex where it may contribute to the stable association of the Nup82 subcomplex with the nuclear pore complex [].Both type 1 (DLC1) and 2 (DLC2) dynein light chains have a similar two-layer α-β core structure consisting of beta-alpha(2)-beta-X-beta(2) [
,
].
This entry represent the first SH3 domain of Nck1. The first SH3 domain of Nck binds the PxxDY sequence in the CD3e cytoplasmic tail; this binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression [
].Nck1 (also called Nck-alpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling [
]. It binds and activates RasGAP, resulting in the downregulation of Ras []. It is also involved in the signaling of endothilin-mediated inhibition of cell migration [].Cytoplasmic proteins Nck are non-enzymatic adaptor proteins composed of three SH3 (Src homology 3) domains and a C-terminal SH2 domain [
]. They regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates []. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics []. They associate with tyrosine-phosphorylated growth factor receptors or their cellular substrates [,
]. There are two vertebrate Nck proteins, Nck1 and Nck2.
Sorting nexin 9 (SNX9) has been suggested to be involved in the endocytic process as an accessory factor [
]. SNX9 has binding sites for both clathrin and adaptor protein AP-2 in a low complexity region, and binds dynamin-2 (Dyn2) by its SH3 domain. SNX9 has its own membrane-binding activity, mediated by a carboxyl-terminal region containing the PX domain and the BAR domain []. Endogenous SNX9 partially co-localizes with AP-2 and Dyn2 at the plasma membrane, and over expression in K562 and HeLa cells of truncated versions of SNX9 inhibits the uptake of transferrin []. Moreover, SNX9 is required for efficient clathrin-mediated endocytosis, which suggests that it functions to regulate dynamin activity [].SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX9 also contains a BAR and a SH3 domain. This entry represents the PX domain of sorting nexin-9. The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions [
].
This entry represents the RING-type zinc finger domain of E3 ubiquitin-protein ligase RNF43. Proteins containing this domain are found in vertebrates. RNF43 acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6 [
,
,
]. RNF43 also interacts with NEDD-4-like ubiquitin-protein ligase-1 (NEDL1) and regulates p53-mediated transcription []. It may also be involved in cell growth control potentially through the interaction with, a chromatin-associated protein interfacing the nuclear envelope []. Mutations of RNF43 have been identified in various tumours, including colorectal cancer (CRC), endometrial cancer, mucinous ovarian tumours, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, liver fluke-associated cholangiocarcinoma, hepatocellular carcinoma, and glioma [,
,
]. RNF43 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C3H2C3-type RING-H2 finger domain followed by a long C-terminal region [].In frogs (Xenopus), ZNRF3 and RNF43 were seen to play a key role in limb specification, constituting a master switch along with RSPO2, which may have implications for regenerative medicine [
].
Hemopexin (
) is a serum glycoprotein that binds haem and transports it to the liver for breakdown and iron recovery, after which the free hemopexin returns to the circulation [
]. Hemopexin prevents haem-mediated oxidative stress. Structurally hemopexin consists of two similar halves of approximately two hundred amino acid residues connected by a histidine-rich hinge region. Each half is itself formed by the repetition of a basic unit of some 35 to 45 residues. Hemopexin-like domains have been found in two other types of proteins, vitronectin [], a cell adhesion and spreading factor found in plasma and tissues, and matrixins MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, MMP-11, MMP-12, MMP-14, MMP-15 and MMP-16, members of the matrix metalloproteinase family that cleave extracellular matrix constituents []. These zinc endopeptidases, which belong to MEROPS peptidase subfamily M10A, have a single hemopexin-like domain in their C-terminal section. It is suggested that the hemopexin domain facilitates binding to a variety of molecules and proteins, for example the HX repeats of some matrixins bind tissue inhibitor of metallopeptidases (TIMPs).
Proteins belonging to the SNF2 family of DNA dependent ATPases are important members of the chromatin remodelling complexes that are implicated in epigenetic control of gene expression. Members of the SNF2 family of proteins
have been identified in organisms ranging from Escherichia coli to Homo sapiens (Human). All of them contain the conserved SNF2 domain, which is defined by the existence of seven motifs (I, Ia, and II-VI) with sequences similarity to those motifs found in DNA and RNA helicases (see ). SNF2-like family members can be further subdivided into several subfamilies according to the presence of protein motifs outside of the ATPase region. The DBINO (DNA binding domain of INO80) domain is characteristic of the INO80 subfamily and is a DNA-binding domain [
,
]. The DBINO domain is a 126 amino acid long peptide located near the N terminus, approximately 100 residues upstream of the SNF2 helicase domain. The presence of this domain in all the INO80 subfamily proteins from yeast to humans suggests its conserved function in evolution [,
].
The OB-fold (oligonucleotide/oligosaccharide-binding fold) is found in all three kingdoms and its common architecture presents a binding face that has adapted to bind different ligands. The OB-fold is a five/six-stranded closed β-barrel formed by 70-80 amino acid residues. The strands are connected by loops of varying length which form the functional appendages of the protein. The majority of OB-fold proteins use the same face for ligand binding or as an active site. Different OB-fold proteins use this 'fold-related binding face' to, variously, bind oligosaccharides, oligonucleotides, proteins, metal ions and catalytic substrates. This entry contains OB-fold domains that bind to nucleic acids [
]. It includes the anti-codon binding domain of lysyl, aspartyl, and asparaginyl-tRNA synthetases (See ). Aminoacyl-tRNA synthetases catalyse the addition of an amino acid to the appropriate tRNA molecule
. This domain is found in RecG helicase involved in DNA repair. Replication factor A is a heterotrimeric complex, that contains a subunit in this family [
,
]. This domain is also found at the C terminus of bacterial DNA polymerase III alpha chain.
The CCAAT-binding factor (CBF, of NFY) is a mammalian transcription factor that binds to a CCAAT motif in the promoters of a wide variety of genes, including type I collagen and albumin. The factor is a heteromeric complex of A and B subunits, both of which are required for DNA-binding [
,
]. The subunits can interact in the absence of DNA-binding, conserved regions in each being important in mediating this interaction.The A subunit can be split into 3 domains on the basis of sequence similarity, a non-conserved N-terminal 'A domain'; a highly-conserved central 'B domain' involved in DNA-binding; and a C-terminal 'C domain', which contains a number of glutamine and acidic residues involved in protein-protein interactions [
]. The A subunit shows striking similarity to the HAP3 subunit of the yeast CCAAT-binding heterotrimeric transcription factor [,
]. The Kluyveromyces lactis HAP3 protein has been predicted to contain a 4-cysteine zinc finger, which is thought to be present in similar HAP3 and CBF subunit A proteins, in which the third cysteine is replaced by a serine [].
CDC50/LEM3 is a family of membrane proteins whose members include cell cycle control protein 50, alkylphosphocholine resistance protein LEM3, which is is required for phospholipid translocation across the plasma membrane in Saccharomyces cerevisiae [
], and several ALA-interacting subunits, which are plant proteins involved in lipid translocation and secretory vesicle formation [,
]. CDC50 (also known as P4-ATPase flippase complex beta subunit TMEM30A) is an accessory component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. It is required for the proper folding, assembly and ER to Golgi exit of the ATP8A2:CDC50A flippase complex, which may be involved in regulation of neurite outgrowth, and, reconstituted to liposomes, predominantly transports phosphatidylserine (PS) and to a lesser extent phosphatidylethanolamine (PE). In complex with ATP8A1, may play a role in regulation of cell migration probably involving flippase-mediated translocation of phosphatidylethanolamine (PE) at the plasma membrane [].
Dynein is a multisubunit microtubule-dependent motor enzyme that acts as the force generating protein of eukaryotic cilia and flagella. The cytoplasmic isoform of dynein acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.Dynein is composed of a number of ATP-binding large subunits (see
), intermediate size subunits and small subunits. Among the small subunits, there is a family of highly conserved proteins which make up this family [
,
,
]. Proteins in this family act as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function and may play a role in changing or maintaining the spatial distribution of cytoskeletal structures. In yeast, it was identified as a component of the nuclear pore complex where it may contribute to the stable association of the Nup82 subcomplex with the nuclear pore complex [].Both type 1 (DLC1) and 2 (DLC2) dynein light chains have a similar two-layer α-β core structure consisting of beta-alpha(2)-beta-X-beta(2) [
,
].
This group represents the yeast phosphoprotein phosphatase, Ppz-type. Ppz proteins function in the regulation of K+ transport. Ppz proteins and the Hal3p inhibitory subunit of Ppz1 are important determinants of salt tolerance, cell wall integrity and cell cycle progression, each of which is dependent upon the Trk K+ transporters [
,
]. The decreased Ppz activity found in Ppz mutants results in the activation of Trk and the subsequent plasma membrane depolarisation (reducing uptake of toxic cations), increased intracellular K+ and turgor (compromising cell integrity), and increased intracellular pH (augmenting the expression of pH-regulated genes and facilitating alpha-factor recovery). Ppz1 orthologues are found only in fungi [].Ppq1 yeast phosphatase consists of two distinct domains: the C-terminal phosphatase domain is approximately 60% identical to either PP1 or the carboxy-terminal domains of PPZ1 and PPZ2, while the N-terminal region is rich in serine and asparagine. Ppq1 seems to be involved in the regulation of protein synthesis [
] and functions as a negative regulator of the mating MAPK pathway [].
Antifreeze proteins (AFPs) are defined by their ability to bind ice and prevent it from growing. In this way they function in both freeze-resistance and freeze-tolerance strategies of organisms that live at sub-zero temperatures and require protection from ice growth. In fish, five AFP types have been described that are remarkably diverse in their 3D structures. They have completely dissimilar folds and no sequence homology. Type III AFPs found in eelpouts are 65-residue proteins with a compact globular fold formed from short β-strands, which presents a flat ice binding surface. These proteins are homologous to the C-terminal region of mammalian and prokaryotic sialic acid synthase (SAS; gene neuB), which has been called AFP-like domain [
]. The similarity is greatest in the protein core and the flat ice-binding region. SAS is involved in the condensation of phosphoenolpyruvate with N-acetylmannosamine derivatives to generate N-acetylneuraminic acid, an intermediate used for the sialylation of glycoconjugates. The function of the AFP-like domain, which is a β-clip fold [], in SAS is not known, but it has been proposed that it could be involved in sugar binding.
This entry represents the Nipped-B protein and its homologues, including Mis4 from fission yeast, Scc2 from budding yeast and Nipbl from zebrafish and Nipped-B from Drosophila. Budding yeast Scc2 is known to be part of the loader for the cohesion to be loaded onto the chromosome [
]. It has also been shown to regulate gene expression independent of cohesin [].Drosophila melanogaster Nipped-B protein is a chromatin binding protein that is involved in sister chromatid cohesion. Nipped-B and its Mau-2 partner are required for cohesin to associate with chromosomes [
]. The Drosophila Nipped-B has also been shown to regulate gene expression []. The zebrafish Nipbl has also been shown to regulate transcription. Nipbl has the ability to interact with other molecules such as histone deacetylases, HP-1gamma, and chromatin remodelling factors. It has been suggested that Nipbl is a cohesin-asociated scaffold protein that have functions other than loading cohesin [
]. Mutations in the human NIPBL (Nipped-B-like) gene cause Cornelia de Lange syndrome 1 (CDLS1), a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems [
].
This entry represents a group of RNA-binding proteins , including Ataxin-2 from animals, Pbp1 from fungi and Cid3/4 from Arabidopsis.
Ataxin-2 has many functions, such as endocytic receptor cycling [
], translational regulation, embryonic development [], energy metabolism and weight regulation []. Mutations of the Ataxin-2 gene cause spinocerebellar ataxia 2 (SCA2), a neurodegenerative disorder leading to predominant loss of Purkinje cells in the cerebellum and impairment of motor coordination []. In SCA2, expansion of a CAG repeat in exon 1 of the Ataxin-2 (ATXN2) gene causes expansion of a polyQ domain in the ATXN2 protein []. ATXN2 has been shown to interact with many proteins. It interacts with multiple RNA-binding proteins (RBPs), staufen, IP3R, RGS8 mRNA, endophilins and CIN85 [].Pbp1 interacts with Pab1 to regulate mRNA polyadenylation [,
]. It promotes mating-type switching in mother cells by positively regulating HO mRNA translation [] and forms a condensate in response to respiratory status to regulate TORC1 signalling []. It is also involved in P-body-dependent granule assembly [].Cid3/4 may have a role in developmental pathways throughout the life cycle of plants [
].
This entry represents the N-terminal Sel1-like repeats found in the wolframin protein. This region has been linked to calmodulin-binding, suggesting these repeats may mediate a protein interaction [
,
].Wolframin, a multi-pass membrane protein found in the endoplasmic reticulum, is expressed by the Wolfram syndrome 1 gene (WFS1) [
]. The detailed molecular function of the protein is not known, but it is believed to participate, at least in part, in the regulation of cellular calcium homeostasis by modulating the filling state of the endoplasmic reticulum calcium store.Defects in WFS1 cause Wolfram Syndrome (WFS), also referred to as DIDMOAD [
] - this syndrome is characterised by diabetes insipidus, childhood-onset diabetes mellitus, gradual loss of vision owing to optic atrophy, and deafness []. It is a rare autosomal recessive disorder, and may give rise to other complications affecting the bladder and nervous system.Wolframin homologues have been identified in a range of species, from mammals and amphibia to insects. Notwithstanding regions of high similarity, vertebrate and invertebrate wolframins exhibit characteristic lineage- specific differences. This entry represents the Wolframin family, and includes homologues from invertebrates.
The capsid of spherical viruses is built from a limited number of proteins and often displays icosahedral symmetry. Rotaviruses have a segmented double-stranded RNA genome enclosed in a complex capsid formed by three concentric protein layers. The proteins forming the capsid are VP2 (internal layer, with triangulation T = 1 and an asymmetric dimer in the icosahedral repeating unit), VP6 (intermediate layer, T = 13 symmetry), VP7 (external layer, T = 13) and VP4, which forms a spike inserted in the outermost two layers. The major capsid protein VP6 self-assembles into spherical or helical particles mainly depending upon pH. VP6 assemblies arise from different pickings of a unique dimer of trimers. The repeating unit of the helix contains a pair of trimers related by a radial dyad []. The VP6 trimer is composed of two domains: a head (external) and a base (internal), leaving a central cavity, these are formed by a distal β-barrel domain and a proximal α-helical domain, which interact with the outer and inner layer of the virion, respectively [].
XRN2 is an essential eukaryotic exoribonuclease that processes and degrades various substrates. The ~80-residue XRN2-binding domain (XTBD) constitutes an XRN2-binding module that is employed by different metazoan proteins to link to XRN2 [
,
], such as:Caenorhabditis elegans Partner of Xrn-Two protein 1, or PAXT-1 for short.
Plays a role in maintenance of steady-state concentration and turnover ofmicroRNAs (miRNA) by degradation of mature miRNA in complex with the
exoribonuclease XRN-2 [].Mammalian CDKN2A-interacting protein (CDKN2AIP) or Collaborator of ARF
(CARF) that regulates DNA damage response in a dose-dependent manner through a number of signaling pathways involved in cell proliferation, apoptosis [,
]. Mammalian CDKN2AIP N-terminal-like protein (CDKN2AIPNL).The XTBD domain folds into a globular four-helix bundle (H1-H4) connected by three loops (L1-L3). H1-H3 form an antiparallel helical array and H4 folds back on top of H2 and H3 at a 90degree angle. The four-helical bundle is mainly stabilized by hydrophobic helix-helix interactions together with additional polar interactions between side chains located on neighbouring helices. The four-helix bundle of XTBD represents a structurally unique arrangement for XRN2 binding [
].
BACH proteins are Cap'n'Collar (CNC) Basic leucine zipper (bZIP) transcription factors that are defined by a conserved 43-amino acid region (called the CNC domain) located N-terminal to the bZIP DNA-binding domain. In addition, they contain a BTB domain (Broad complex-Tramtrack-Bric-a-brac domain, also known as the POZ [poxvirus and zinc finger] domain) that is absent in other CNC proteins. Veterbrates contain two members, BACH1 and BACH2. BACH1 forms heterodimers with small Mafs such as MafK to function as a repressor of heme oxygenase-1 (HO-1) gene (Hmox-1) enhancers [
]. It has also been implicated as the master regulator of breast cancer bone metastasis []. The BACH1 bZIP transcription factor should not be confused with the protein originally named as BRCA1-Associated C-terminal Helicase1 (BACH1), which has been renamed BRIP1 (BRCA1 Interacting Protein C-terminal Helicase1) and also called FANCJ. BACH2 is a B-cell specific transcription factor that plays a critical role in oxidative stress-mediated apoptosis []. It plays an important role in class switching and somatic hypermutation of immunoglobulin genes [].
This entry represents a group of proteins belonging to the HpcH/HpaI aldolase family. Proteins in this entry include citrate lyase subunit beta, malyl-CoA lyase and (3S)-malyl-CoA thioesterase. This entry also includes beta-methylmalyl-CoA lyase (rrnAC0690) from Haloarcula marismortui. Citrate lyase catalyses the magnesium-dependent cleavage of citrate to acetate and oxaloacetate. In bacteria, this reaction is involved in citrate fermentation. The bacterial enzyme is composed of three subunits: alpha, beta and gamma. Catalytic activity resides on the alpha- and beta-subunits, whereas the gamma-subunit serves as an acyl carrier protein (ACP) [
]. Mammalian citrate lyase beta proteins display similarity to the bacterial enzymes [].Malyl-CoA lyase catalyses the reversible condensation of glyoxylate and acetyl-CoA to L-malyl-CoA and the reversible condensation of glyoxylate and propionyl-CoA to beta-methylmalyl-CoA [
]. (3S)-malyl-CoA thioesterase catalyses the hydrolysis of (3S)-malyl-CoA to (3S)-malate and free CoA [
]. Haloarcula marismortui beta-methylmalyl-CoA lyase may be involved in the methylaspartate cycle [
]. It catalyses the reversible cleavage of beta-methylmalyl-CoA to propionyl-CoA and glyoxylate, as well as the reversible cleavage of (S)-malyl-CoA to acetyl-CoA and glyoxylate with some (S)-malyl-CoA thioesterase activity [].
The DAPIN (Domain in Apoptosis and INterferon response) domain is an 80-100-
residue domain which is found in the N terminus of diverse vertebrate andvertebrate-specific viral proteins involved in apoptosis, cancer,
inflammation, and immune response. The DAPIN domain can be found alone or inassociation with other domains [
,
,
] like CARD, LRR, SPRY, Caspase or Zinc finger B-box. It has been proposed that the DAPIN domain might have an adaptor function, coupling apoptosis and immune disorders [,
,
]. It has been shown that the DAPIN domain is a protein-protein interaction domain capable of binding to other DAPIN domains [].Secondary structure predictions have identified the DAPIN domain as mostly
α-helical and it has been suggested that it could belong to the DEATH-domain-fold superfamily, which includes the CARD, the DEATH domain (DD) and the DEATH effector domain (DED) [
,
,
].The DAPIN domain has also been called pyrin domain, pyrin N-terminal homology
domain (PYD) or PAAD (after the protein families pyrin, AIM, ASC death-domain-like) [
,
].
Phasins (or granule-associate proteins) are surface proteins found covering Polyhydroxyalkanoate (PHA) storage granules in bacteria. Polyhydroxyalkanoates are linear polyesters produced by bacterial fermentation of sugar or lipids for the purpose of storing carbon and energy, and are accumulated as intracellular granules by many bacteria under unfavorable conditions, enhancing their fitness and stress resistance [
]. The layer of phasins stabilises the granules and prevents coalescence of separated granules in the cytoplasm and nonspecific binding of other proteins to the hydrophobic surfaces of the granules. For example, in Ralstonia eutropha (strain ATCC 17699/H16/DSM 428/Stanier 337) (Cupriavidus necator (strain ATCC 17699 / H16 / DSM 428 / Stanier 337)), the major surface protein of polyhydroxybutyrate (PHB) granules is phasin PhaP1(Reu), which occurs along with three homologues (PhaP2, PhaP3, and PhaP4) that have the capacity to bind to PHB granules but are present at minor levels [,
]. These four phasins lack a highly conserved domain but share homologous hydrophobic regions. This entry describes a group of phasins that associate with polyhydroxyalkanoate (PHA) inclusions, the most common of which consist of polyhydroxybutyrate (PHB).
This domain is found in animal PIH1 domain-containing protein 1/2/3 (PIH1D1/2/3) and its homologues [
]. PIH1D1 is part of the HSP90 co-chaperone R2TP complex involved in the assembly process of many molecular machines []. This domain consists of a seven-stranded beta sandwich with the topology of a CS domain, a structural motif also found in Hsp90 co-chaperones such as p23/Sba1 and Sgt1 []. Proteins containing this domain also includes Kintoun from animals and uncharacterised proteins from fungi and plants. Kintoun (also known as ktu or dynein assembly factor 2, axonemal) is a cytoplasmic protein conserved from ciliated unicellular organisms to mammals. It is required for cytoplasmic pre-assembly of axonemal dynein arm complexes before intraflagellar transport loads them for the ciliary compartment. Its homologue in single-celled alga Chlamydomonas is known as PF13. A mutation in Ktu/PF13 has been identified in some patients with primary ciliary dyskinesia (PCD). In the absence of Ktu/PF13, both dynein arms (inner and outer) are missing or defective in the axoneme, leading to a loss of motility [].
This entry represents the SET domain of SET and MYND domain-containing protein 2 (SMYD2). SMYD2 functions as a histone methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1 [
,
]. It specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). It plays a role in myofilament organisation in both skeletal and cardiac muscles via Hsp90 methylation []. SMYD2 overexpression is associated with tumour cell proliferation and a worse outcome in human papillomavirus-unrelated nonmultiple head and neck carcinomas []. It regulates leukemia cell growth such that diminished SMYD2 expression upregulates SET7/9, thereby possibly shifting leukemia cells from growth to quiescence state associated with resistance to DNA damage associated with Acute Myeloid Leukemia (AML) [].The SMYD family consists of five members including SMYD1/2/3/4/5. They contain two highly conserved structural and functional domains, the SET and MYND domains. The SET domain is involved in lysine methylation, while the MYND domain is involved in protein-protein interaction. They are essential in several mammalian developmental pathways [
,
,
,
].
Sorting nexin 9 (SNX9) has been suggested to be involved in the endocytic process as an accessory factor [
]. SNX9 has binding sites for both clathrin and adaptor protein AP-2 in a low complexity region, and binds dynamin-2 (Dyn2) by its SH3 domain. SNX9 has its own membrane-binding activity, mediated by a carboxyl-terminal region containing the PX domain and the BAR domain []. Endogenous SNX9 partially co-localizes with AP-2 and Dyn2 at the plasma membrane, and over expression in K562 and HeLa cells of truncated versions of SNX9 inhibits the uptake of transferrin []. Moreover, SNX9 is required for efficient clathrin-mediated endocytosis, which suggests that it functions to regulate dynamin activity [].SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX9 also contains a BAR and a SH3 domain. This entry represents the BAR domain of sorting nexin-9. BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions [
].
Lectins are structurally diverse proteins that bind to specific carbohydrates. This family includes the VIP36 and ERGIC-53 lectins. These two proteins were the first members of the family of animal lectins similar to the leguminous plant lectins [
]. The alignment for this family is towards the N terminus, where the similarity of VIP36 and ERGIC-53 is greatest. Although they have been identified as a family of animal lectins, this alignment also includes yeast sequences[]. ERGIC-53 is a 53kDa protein, localised to the intermediate region between the endoplasmic reticulum and the Golgi apparatus (ER-Golgi-Intermediate Compartment, ERGIC). It was identified as a calcium-dependent, mannose-specific lectin [
]. Its dysfunction has been associated with combined factors V and VIII deficiency, suggesting an important and substrate-specific role for ERGIC-53 in the glycoprotein-secreting pathway [,
].The L-type lectin-like domain has an overall globular shape composed of a β-sandwich of two major twisted antiparallel β-sheets. The β-sandwich comprises a major concave β-sheet and a minor convex β-sheet, in a variation of the jelly roll fold [
,
,
,
].
Subunits of the vesicle tethering complex (such as Tip20 and Dsl1) share protein sequence similarity with known subunits of the exocyst complex, establishing a structural connection among several multi-subunit tethering complexes and implying that many of their subunits are derived from a common progenitor. Proteins containing this domain includes EXOC6/PINT-1 from animals, Tip20 from budding yeast, Sec15 from fission yeasts and MAIGO2 (Mag2) from plants. Sec15 (EXOC6 homologue) is an exocyst complex component that links Sec4 and downstream fusion effectors at discrete cellular locations. Its C-terminal domain mediates Rab GTPases binding which occurs in a GTP-dependent manner [
]. PINT-1/Tip20/MAIGO2 play a role in anterograde transport from the endoplasmic reticulum (ER) to the Golgi and/or retrograde transport from the Golgi to the ER. They share a similar domain organisation with an N-terminal leucine heptad repeat rich coiled coil and an ~500-residue C-terminal RINT1/TIP20 domain, which might be a protein-protein interaction module necessary for the formation of functional complexes. This superfamily represents the domain 1 found in the C-terminal domain of the exocyst complex subunit Sec15.
The type III secretion system of Gram-negative bacteria is used to transport virulence factors from the pathogen directly into the host cell [
] and is only triggered when the bacterium comes into close contact with the host. Effector proteins secreted by the type III system do not possess a secretion signal, and are considered unique because of this. Salmonella spp. secrete an effector protein called SopE that is responsible for stimulating
the reorganisation of the host cell actin cytoskeleton, and ruffling of the cellular membrane [
]. It acts as a guanyl-nucleotide-exchange factor on Rho-GTPase proteins such as Cdc42 and Rac. As it is imperative for the bacterium to revert the cell back to its "normal"state as quickly as possible,
another tyrosine phosphatase effector called SptP reverses the actions brought about by SopE [
]. SopE and its protein homologue SopE2 can
activate different sets of Rho-GTPases in the host cell []. Far from being a redundant set of two similar type III effectors, they both act in unison to specifically activate different Rho-GTPase signalling cascades in the
host cell during infection.
Members of this protein family belong to the family of bacterial sugar transferases (
). Nearly all are found in species that encode the PEP-CTERM/exosortase system predicted to act in protein sorting in a number of Gram-negative bacteria (notable exceptions appear to include Magnetococcus sp. (strain MC-1) and Myxococcus xanthus (strain DK 1622)). These genes are generally found near one or more of the PrsK, PrsR or PrsT genes that have been related to the PEP-CTERM system by phylogenetic profiling methods. The nature of the sugar transferase reaction catalysed by members of this clade is unknown and may conceivably be variable with respect to substrate by species. These proteins are homologues of the EpsB protein found in Methylobacillus sp. 12S [
], which is also associated with a PEP-CTERM system, but of a distinct type. A name which appears attached to a number of genes (by transitive annotation) in this family is "undecaprenyl-phosphate galactose phosphotransferase", which comes from relatively distant characterised enterobacterial homologues, and is considerably more specific than warranted from the currently available evidence.
Sufu, encoding the human ortholog of Drosophila suppressor of fused, appears to have a conserved role in the repression of Hedgehog signalling [
]. It is a repressor of the Gli and Ci transcription factors of the Hedgehog signalling cascade [], and functions by binding these proteins and preventing their translocation to the nucleus. Sufu has been found to be a tumour-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signalling pathway []. Homologues of Sufu have been found in bacteria, though their function is not currently known.This entry represents a domain found in Sufu and its homologues. It is also found in other proteins that are functionally uncharacterised. In eukaryotic Sufu, an additional domain (
) is found at the C terminus of the protein. This domain binds to the C-terminal domain of the Gli/Ci transcription factors, inhibiting their activity [
].This domain is also found in Immunity protein YqcF from B. subtilis, a component of one of 6 LXG toxin-immunity modules. It neutralizes the toxic activity of cognate toxin YqcG [
, ].
Aurora kinase was discovered by Glover and colleagues in a screen for genes required to maintain the centrosome cycle in Drosophila [
]. Its yeast homologue Ipl1 (also known as spindle assembly checkpoint kinase) was found to regulate chromosome segregation []. Subsequently, three mammal Aurora kinases, Aurora A, B and C, have been identified. They are highly conserved serine/threonine kinases that regulate chromosomal alignment and segregation during mitosis and meiosis [
]. They all contain a protein kinase domain and a destruction box (D-box) recognised by the multi-subunit E3-ubiquitin ligase anaphase promoting complex/cyclosome (APC/C), which mediates their proteasomal degradation. However, their N-terminal domains share little sequence identity and confer unique protein-protein interaction abilities among the Aurora kinases []. Functionally, Aurora A associates with centrosome, while Aurora B and Aurora C are parts of the chromosome passenger complex (CPC) [
,
]. Aurora C plays a role in the meiotic cell cycle, but does not seem to be essential for cell divisions in somatic cells [
]. This entry also includes a number of uncharacterised proteins, predominantly from bacteria.
Electron transfer flavoprotein subunit alpha, conserved site
Type:
Conserved_site
Description:
Electron transfer flavoproteins (ETFs) serve as specific electron acceptors for primary dehydrogenases, transferring the electrons to terminal respiratory systems. They can be functionally classified into constitutive, "housekeeping"ETFs, mainly involved in the oxidation of fatty acids (Group I), and ETFs produced by some prokaryotes under specific growth conditions, receiving electrons only from the oxidation of specific substrates (Group II) [
]. ETFs are heterodimeric proteins composed of an alpha and beta subunit, and contain an FAD cofactor and AMP [
,
,
,
,
]. ETF consists of three domains: domains I and II are formed by the N- and C-terminal portions of the alpha subunit, respectively, while domain III is formed by the beta subunit. Domains I and III share an almost identical α-β-alpha sandwich fold, while domain II forms an α-β-alpha sandwich similar to that of bacterial flavodoxins. FAD is bound in a cleft between domains II and III, while domain III binds the AMP molecule. Interactions between domains I and III stabilise the protein, forming a shallow bowl where domain II resides.This entry represents the conserved site of the C-terminal domain of the alpha subunit of both Group I and Group II electron transfer flavoproteins.
Ketosamines derive from a non-enzymatic reaction between a sugar and a protein [
]. Ketosamine-3-kinases (KT3K), of which fructosamine-3-kinase (FN3K) is the best-known example, catalyse the phosphorylation of the ketosamine moiety of glycated proteins. The instability of a phosphorylated ketosamine leads to its degradation, and KT3K is thus thought to be involved in protein repair [].The function of the prokaryotic members of this group has not been established. However, several lines of evidence indicate that they may function as fructosamine-3-kinases (FN3K). First, they are similar to characterised FN3K from mouse and human. Second, the Escherichia coli members are found in close proximity on the genome to fructose-6-phosphate kinase (PfkB). Last, FN3K activity has been found in a Anacystis montana (Gloeocapsa montana Kutzing 1843) [], indicating such activity-directly demonstrated in eukaryotes-is nonetheless not confined to eukaryotes.This family includes eukaryotic fructosamine-3-kinase enzymes [
] which may initiate a process leading to the deglycation of fructoselysine and of glycated proteins and in the phosphorylation of 1-deoxy-1-morpholinofructose, fructoselysine, fructoseglycine, fructose andglycated lysozyme. The family also includes bacterial members that have not been characterised but probably have a similar or identical function.
Initiation factor 2 (IF-2) (gene infB) [
] is one of the three factorsrequired for the initiation of protein biosynthesis in bacteria. IF-2
promotes the GTP-dependent binding of the initiator tRNA to the small subunitof the ribosome. IF-2 is a protein of about 70 to 95 Kd which contains a
central GTP-binding domain flanked by a highly variable N-terminal domain anda more conserved C-terminal domain.
Bacterial IF-2 is structurally and functionally related to eukaryoticmitochondrial IF-2 (IF-2(mt)) [
] as well as to algal and plants chloroplastIF-2 (IF-2(chl)). Both IF-2(mt) and IF-2(chl) are encoded by nuclear genes and
are produced as precursor proteins with a transit peptide. An exception arered algae where IF-2(chl) is encoded by the plastid genome [
].This model discriminates eubacterial (and mitochondrial) translation initiation factor 2 (IF-2), encoded by the infB gene in bacteria, from similar proteins in the Archaea and Eukaryotes. In the bacteria and in organelles, the initiator tRNA is charged with N-formyl-Met instead of Met. This translation factor acts in delivering the initator tRNA to the ribosome. It is one of a number of GTP-binding translation factors recognised by the pfam HMM GTP_EFTU.
This entry groups metazoan phosphatidylethanolamine-binding proteins, carboxypeptidase Y inhibitor from Saccharomyces cerevisiae (Baker's yeast) (), and homologues from plants which function in flower development. The members of this family belong to MEROPS proteinase inhibitor family I51, clan I-.
In metazoa the phosphatidylethanolamine-binding proteins are an around 200 residue and found in a variety of tissues [
]. They bind hydrophobic ligands, such as phosphatidylethanolamine, but also seems [] to bind nucleotides such as GTP and FMN, it has been suggested that they could act in membrane remodelling during growth and maturation.In plants, the phosphatidylethanolamine-binding protein homologues, include:CENTRORADIALIS (CEN) [
]
SELF PRUNING (SP) [
] TERMINAL FLOWER 1 (TFL1) FLOWERING LOCUS T (FT) MOTHER OF FT AND TFL1 (MTF) [
]
In Arabidopsis thaliana (Mouse-ear cress), FT together with LEAFY (LFY),
, promote flowering and are positively regulated by the transcription factor CONSTANS (CO). Loss of FT causes delay in flowering, whereas over expression of FT results in precocious flowering independent of CO or photoperiod. FT acts in part downstream of CO and mediates signals for flowering in an antagonistic manner with its homologous gene, TERMINAL FLOWER1 (TFL1) [
].
These metallopeptidases belong to MEROPS peptidase family M16 (clan ME). They include proteins, which are classified as non-peptidase homologues either have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for the catalytic activity. The peptidases in this group of sequences include:Insulinase, insulin-degrading enzyme (
)
Mitochondrial processing peptidase alpha subunit, (Alpha-MPP,
)
Pitrlysin, Protease III precursor (
)
Nardilysin, (
)
Ubiquinol-cytochrome C reductase complex core protein I,mitochondrial precursor (
)
Coenzyme PQQ synthesis protein F (
)
These proteins do not share many regions of sequence similarity; the most noticeable is in the N-terminal section. This region includes a conserved histidine followed, two residues later by a glutamate and another histidine. In pitrilysin, it has been shown [
] that this H-x-x-E-H motif is involved in enzymatic activity; the two histidines bind zinc and the glutamate is necessary for catalytic activity. The mitochondrial processing peptidase consists of two structurally related domains. One is the active peptidase whereas the other, the C-terminal region, is inactive. The two domains hold the substrate like a clamp [].
A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been shown [
,
,
,
,
] to be present in a large number of membrane-bound and extracellular, mostly animal, proteins. Many of these proteins require calcium for their biological function and a calcium-binding site has been found at the N terminus of some EGF-like domains []. Calcium-binding may be crucial for numerous protein-protein interactions.For human coagulation factor IX it has been shown [
] that the calcium-ligands form a pentagonal bipyramid. The first, third and fourth conserved negatively charged or polar residues are side chain ligands. The latter is possibly hydroxylated (see aspartic acid and asparagine hydroxylation site) []. A conserved aromatic residue, as well as the second conserved negative residue, are thought to be involved in stabilising the calcium-binding site.As in non-calcium binding EGF-like domains, there are six conserved cysteines and the structure of both types is very similar as calcium-binding induces only strictly local structural changes [
].+------------------+ +---------+
| | | |nxnnC-x(3,14)-C-x(3,7)-CxxbxxxxaxC-x(1,6)-C-x(8,13)-Cx
| | +------------------+
'n': negatively charged or polar residue [DEQN]'b': possibly beta-hydroxylated residue [DN]
'a': aromatic amino acid'C': cysteine, involved in disulphide bond
'x': any amino acid.
A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been shown [
,
,
,
,
] to be present in a large number of membrane-bound and extracellular, mostly animal, proteins. Many of these proteins require calcium for their biological function and a calcium-binding site has been found at the N terminus of some EGF-like domains []. Calcium-binding may be crucial for numerous protein-protein interactions.For human coagulation factor IX it has been shown [
] that the calcium-ligands form a pentagonal bipyramid. The first, third and fourth conserved negatively charged or polar residues are side chain ligands. The latter is possibly hydroxylated (see aspartic acid and asparagine hydroxylation site) []. A conserved aromatic residue, as well as the second conserved negative residue, are thought to be involved in stabilising the calcium-binding site.As in non-calcium binding EGF-like domains, there are six conserved cysteines and the structure of both types is very similar as calcium-binding induces only strictly local structural changes [
].+------------------+ +---------+
| | | |
nxnnC-x(3,14)-C-x(3,7)-CxxbxxxxaxC-x(1,6)-C-x(8,13)-Cx| |
+------------------+'n': negatively charged or polar residue [DEQN]
'b': possibly beta-hydroxylated residue [DN]'a': aromatic amino acid
'C': cysteine, involved in disulphide bond'x': any amino acid.
Aconitase (aconitate hydratase) [
] is the enzyme from the tricarboxylic acid cycle that catalyzes the reversible isomerization of citrate and isocitrate. Cis-aconitate is formed as an intermediary product during the course of the reaction. In eukaryotes two isozymes of aconitase are known to exist: one found in the mitochondrial matrix and the other found in the cytoplasm. Aconitase, in its active form, contains a 4Fe-4S iron-sulphur cluster; three cysteine residues have been shown to be ligands of the 4Fe-4S cluster. It has been shown that the aconitase family also contains the following proteins: Iron-responsive element binding protein (IRE-BP). IRE-BP is a cytosolic protein that binds to iron-responsive elements (IREs). IREs are stem-loop structures found in the 5'UTR of ferritin, and delta aminolevulinic acid synthase mRNAs, and in the 3'UTR of transferrin receptor mRNA. 3-isopropylmalate dehydratase (
) (isopropylmalate isomerase), the enzyme that catalyzes the second step in the biosynthesis of leucine.
Homoaconitase (
) (homoaconitate hydratase), an enzyme that participates in the alpha-aminoadipate pathway of lysine biosynthesis and that converts cis-homoaconitate into homoisocitric acid.
Esherichia coli protein YbhJ. The signatures in this entry, identify the cysteine residues involved in the binding of the 4Fe-4S iron-sulphur cluster.
This domain is found in a number of functionally different proteins:NusB a prokaryotic transcription factor involved in antiterminationTIM44, the mitochondrial inner membrane translocase subunit RsmB, the 16S rRNA m5C967 methyltransferaseNusB is a prokaryotic transcription factor involved in antitermination processes, during which it interacts with the boxA portion of the mRNA nut site. Previous studies have shown that NusB exhibits an all-helical fold, and that the protein from Escherichia coli forms monomers, while Mycobacterium tuberculosis NusB is a dimer. The functional significance of NusB dimerization is unknown.
An N-terminal arginine-rich sequence is the probable RNA binding site, exhibiting aromatic residues as potential stacking partners for the RNA bases. The RNA binding region is hidden in the subunit interface of dimeric NusB proteins, such as NusB from M. tuberculosis, suggesting that such dimers have to undergo a considerable conformational change or dissociate for engagement with RNA. In certain organisms, dimerization may be employed to package NusB in an inactive form until recruitment into antitermination complexes [,
].The antitermination proteins of E. coli are recruited in the replication cycle of
Bacteriophage lambda, where they play an important role in switching from thelysogenic to the lytic cycle.
Endocytosis and intracellular transport involve several mechanistic steps:
(1) for the internalisation of cargo molecules, the membrane needs to bend to form a vesicular structure, which requires membrane curvature and a rearrangement of the cytoskeleton; (2) following its formation, the vesicle has to be pinched off the membrane; (3) the cargo has to be subsequently transported through the cell and the vesicle must fuse with the correct cellular compartment.Members of the Amphiphysin protein family are key regulators in the early steps of endocytosis, involved in the formation of clathrin-coated vesicles by promoting the assembly of a protein complex at the plasma membrane and directly assist in the induction of the high curvature of the membrane at the neck of the vesicle. Amphiphysins contain a characteristic domain, known as the BAR (Bin-Amphiphysin-Rvs)-domain, which is required for their in vivofunction and their ability to tubulate membranes [
]. The crystal structure of these proteins suggest the domain forms a crescent-shaped dimer of a three-helix coiled coil with a characteristic set of conserved hydrophobic, aromatic and hydrophilic amino acids. Proteins containing this domain have been shown to homodimerise, heterodimerise or, in a few cases, interact with small GTPases.
This group of proteins includes Rad10 from budding yeasts, Swi10 from fission yeasts and ERCC-1 from animals and plants. All proteins in this family for which functions are known are components in a multiprotein endonuclease complex (usually made up of Rad1 and Rad10 homologues). This complex is used primarily for nucleotide excision repair but also for some aspects of recombination repair. In budding yeast, Rad10 works as a heterodimer with Rad1, and is involved in nucleotide excision repair of DNA damaged with UV light, bulky adducts or cross-linking agents. The complex forms an endonuclease which specifically degrades single-stranded DNA [
].ERCC1 and XPF (xeroderma pigmentosum group F-complementing protein) are two structure-specific endonucleases of a class of seven containing an ERCC4 domain. Together they form an obligate complex that functions primarily in nucleotide excision repair (NER), a versatile pathway able to detect and remove a variety of DNA lesions induced by UV light and environmental carcinogens, and secondarily in DNA inter-strand cross-link repair and telomere maintenance. This domain in fact binds simultaneously to both XPF and single-stranded DNA; this ternary complex explains the important role of Ercc1 in targeting its catalytic XPF partner to the NER pre-incision complex [
].
The MADF (myb/SANT-like domain in Adf-1) domain is an approximately 80-amino-acid module that directs sequence specific DNA binding to a site consisting of multiple tri-nucleotide repeats. The MADF domain is found in one or more copies in eukaryotic and viral proteins and is often associated with the BESS domain [
]. MADF is related to the Myb DNA-binding domain (). The retroviral oncogene v-myb, and its cellular counterpart c-myb, are nuclear DNA-binding proteins that specifically recognise the sequence YAAC(G/T)G. It is likely that the MADF domain is more closely related to the myb/SANT domain than it is to other HTH domains. Some proteins known to contain a MADF domain are listed below: Drosophila Adf-1, a transcription factor first identified on the basis of its interaction with the alcohol dehydrogenase promoter but that binds the promoters of a diverse group of genes [
]. Drosophila Dorsal-interacting protein 3 (Dip3), which functions both as an activator to bind DNA in a sequence specific manner and a coactivator to stimulate synergistic activation by Dorsal and Twist [
]. Drosophila Stonewall (Stwl), a putative transcription factor required for maintenance of female germline stem cells as well as oocyte differentiation.
The glycine-tyrosine-phenylalanine (GYF) domain is an around 60-amino acid domain which contains a conserved GP[YF]xxxx[MV]xxWxxx[GN]YF motif. It was identified in the human intracellular protein termed CD2 binding protein 2 (CD2BP2), which binds to a site containing two tandem PPPGHR segments within the cytoplasmic region of CD2. Binding experiments and mutational analyses have demonstrated the critical importance of the GYF tripeptide in ligand binding. A GYF domain is also found in several other eukaryotic proteins of unknown function []. It has been proposed that the GYF domain found in these proteins could also be involved in proline-rich sequence recognition [].Resolution of the structure of the CD2BP2 GYF domain by NMR spectroscopy revealed a compact domain with a β-β-α-β-beta topology, where the single α-helix is tilted away from the twisted, anti-parallel β-sheet. The conserved residues of the GYF domain create a contiguous patch of predominantly hydrophobic nature which forms an integral part of the ligand-binding site [
]. There is limited homology within the C-terminal 20-30 amino acids of various GYF domains, supporting the idea that this part of the domain is structurally but not functionally important [].
The C2 domain is a Ca
2+-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C and the protein kinase catalytic domain [
]. Regions with significant homology [] to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding [] and in membrane targetting processes such as subcellular localisation. The 3D structure of the C2 domain of synaptotagmin has been reported
[], the domain forms an eight-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key []. Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca2+-binding loops are located at the end of an 8 stranded antiparallel β-sandwich.
Gelsolin is an actin-modulating protein that severs F-actin, caps the barbed ends of actin filaments preventing monomer exchange, and promotes the nucleation step of actin polymerisation [
,
]. It can be regulated by Ca2+ and phosphoinositides []. The interaction between gelsolin and tropomyosin modulates actin dynamics []. Gelsolin also plays a role in ciliogenesis []. The structure of gelsolin has been solved []. Villin is an actin-binding protein that is found in a variety of tissues. It is able to bind to the barbed end of actin filaments with high affinity and can sever filaments [
]. In addition, villin's activity is important for actin bundling in certain cell types []. It was first isolated as a major component of the core of intestinal microvilli [].Villin/gelsolin family includes other actin-binding proteins such as severin and supervillin [
]. Six large repeating segments occur in gelsolin and villin, and 3 similar segments in severin and fragmin. While the multiple repeats have yet to be related to any known function of the actin-severing proteins, the superfamily appears to have evolved from an ancestral sequence of 120 to 130 amino acid residues [].
The DAG-kinase catalytic domain or DAGKc domain is present in mammalian lipid kinases, such as diacylglycerol (DAG), ceramide and sphingosine kinases, as well as in related bacterial proteins [
,
]. Eukaryotic DAG-kinase () catalyses the phosphorylation of DAG to phosphatidic acid, thus modulating the balance between the two signaling lipids. At least ten different isoforms have been identified in mammals, which form 5 groups characterised by different functional domains, such as the calcium-binding EF hand (see
), PH (see ), SAM (see
) , DAG/PE-binding C1 domain (see
) and ankyrin repeats (see
) [
]. In bacteria, an integral membrane DAG kinase forms a homotrimeric protein that lacks the DAGKc domain (see
). In contrast, the bacterial yegS protein is a soluble cytosolic protein that contains the DAGKc domain in the N-terminal part. YegS is a lipid kinase with two structural domains, wherein the active site is located in the interdomain cleft, C-terminal to the DAGKc domain which forms an alpha/beta fold [
]. The tertiary structure resembles that of NAD kinases and contains a metal-binding site in the C-terminal region [,
]. This domain is usually associated with an accessory domain (see
).
Activator of Hsp90 ATPase homologue 1-like, C-terminal
Type:
Domain
Description:
This entry represents a domain found in eukaryotic, prokaryotic and archaeal proteins that bear similarity to a C-terminal region of human activator of 90kDa heat shock protein ATPase homologue 1 (AHSA1/p38,
) and Aha1 from yeast [
,
]. This is a START-like domain (also referred to as SRPBCC domain which stands for START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) which interacts with, and stabilizes the hydrophobic binding groove exposed after the interaction between the N-terminal domain of Aha1 () and the middle domain of Hsp90 [
,
]. SRPBCC domains have a deep hydrophobic ligand-binding pocket. This domain is found repeated in two members of this entry (and
).
AHSA1/Aha1 are known to interact with the middle domain of Hsp90, and stimulate its ATPase activity [
,
], one Aha1 molecule per Hsp90 dimer is sufficient for a full stimulation of Hsp90. It is probably a general up regulator of Hsp90 function, particularly contributing to its efficiency in conditions of increased stress []. AHSA1 is also known to interact with the cytoplasmic domain of the VSV G protein, and may thus be involved in protein transport []. It has also been reported as being under expressed in Down's syndrome.
This entry represents the RPW8 domain found in several broad-spectrum mildew resistance proteins from Arabidopsis thaliana and other dicots. Plant disease resistance (R) genes control the recognition of specific pathogens and activate subsequent defence responses. The R protein-mediated defences typically involve a rapid, localized necrosis, or hypersensitive response (HR), at the site of infection, and the localised formation of antimicrobial chemicals and proteins that restrict growth of the pathogen. The A. thaliana locus Resistance to Powdery Mildew 8 (RPW8) contains two naturally polymorphic, dominant R genes: RPW8.1 and RPW8.2, which individually control resistance to a broad range of powdery mildew pathogens. They induce localised, salicylic acid-dependent defences similar to those induced by R genes that control specific resistance. Apparently, broad-spectrum resistance mediated by RPW8 uses the same mechanisms as specific resistance [
,
]. RPW8.1 and RPW8.2 share similarity with an ~150 amino acid module forming the N terminus of a group of disease resistance proteins, which have a nucleotide-binding site (NBS) and leucine-rich repeats (LRRs) [,
].The RPW8 domain sequences contain a predicted N-terminal transmembrane (TM) region or possibly a signal peptide, and a coiled-coil (CC) motif [
].
The PCI (for Proteasome, COP9, Initiation factor 3) domain (sometimes also
referred to as the PINT domain, for Proteasome subunits, Int-6, Nip-1, andTrip-15) is present in six different subunits of 26 proteasome lid, COP9
signalosome (CSN) and eukaryotic translation initiation factor-3 (eIF3)complexes, as well as in subunits of certain other multiprotein complexes. The
PCI domain mediates and stabilizes protein-protein interactions within thecomplexes. The role of the PCI domains is most likely that of a scaffold for
the other complex subunits and other binding partners. The PCI domain couldplay a role as a universal binding domain supporting intra-complex
interactions as well as recruitments of additional ligands [,
,
,
,
,
].PCI is an ~190-amino acid domain, not well conserved in its primary sequence,
usually located near the C terminus of the protein. It does not contain anyinvariant residues or any conserved pattern of charged residues that would
suggest a catalytic activity. The PCI domain is comprised of two subdomainsthat are intimately connected, an N-terminal helical bundle (HB) subdomain and
a C-terminal globular winged helix (WH) subdomain. The C-terminal half of the PCI domain is much better conserved than the N-terminal
half [,
,
].
Phosphoglycerate/bisphosphoglycerate mutase, active site
Type:
Active_site
Description:
Phosphoglycerate mutase (
) (PGAM) and bisphosphoglycerate mutase (
)
(BPGM) are structurally related enzymes that catalyse reactions involving the transfer of phospho groups between the three carbon atoms of phosphoglycerate [
,
,
]. Both enzymes can catalyse three different reactions with different specificities, the isomerization of 2-phosphoglycerate (2-PGA) to 3-phosphoglycerate (3-PGA) with 2,3-diphosphoglycerate (2,3-DPG) as the primer of the reaction, the synthesis of 2,3-DPG from 1,3-DPG with 3-PGA as a primer and the degradation of 2,3-DPG to 3-PGA (phosphatase activity).
In mammals, PGAM is a dimeric protein with two isoforms, the M (muscle) and B (brain) forms. In yeast, PGAM is a tetrameric protein.BPGM is a dimeric protein and is found mainly in erythrocytes where it plays a major role in regulating haemoglobin oxygen affinity as a consequence of controlling 2,3-DPG concentration. The catalytic mechanism of both PGAM and BPGM involves the formation of a phosphohistidine intermediate [
].A number of other proteins including, the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase [
] that catalyses both the synthesis and the degradation of fructose-2,6-bisphosphate and bacterial alpha-ribazole-5'-phosphate phosphatase, which is involved in cobalamin biosynthesis, belong to this family [].This entry contains the active site phosphohistidine residue.
The post-translational attachment of ubiquitin (
) to proteins (ubiquitinylation) alters the function, location or trafficking of a protein, or targets it to the 26S proteasome for degradation [
,
,
]. Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2, ), and a ubiquitin ligase (E3,
,
), which work sequentially in a cascade [
]. The E1 enzyme is responsible for activating ubiquitin, the first step in ubiquitinylation. The E1 enzyme hydrolyses ATP and adenylates the C-terminal glycine residue of ubiquitin, and then links this residue to the active site cysteine of E1, yielding a ubiquitin-thioester and free AMP. To be fully active, E1 must non-covalently bind to and adenylate a second ubiquitin molecule. The E1 enzyme can then transfer the thioester-linked ubiquitin molecule to a cysteine residue on the ubiquitin-conjugating enzyme, E2, in an ATP-dependent reaction.This entry includes Ubiquitin-activating enzyme E1 (Uba1), SUMO-activating enzyme subunit 1 (Sae1) and similar proteins from eukaryotes. Sae1 is an heterodimer that acts as an E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4 and mediates ATP-dependent activation of SUMO proteins [
,
,
].
This entry represents the C-terminal domain of Sec3 (also known as ExoC1), a component of the exocyst complex (composed of Exoc1, Exoc2, Exoc3, Exoc4, Exoc5, Exoc6, Exoc7 and Exoc8) which mediates the tethering of post-Golgi secretory vesicles to the plasma membrane and promotes the assembly of the SNARE complex for membrane fusion. The exocyst is also involved in other cell processes such as cell polarisation, primary ciliogenesis, cytokinesis, and tumorigenesis and metastasis [
]. This complex has an elongated shape consisting of packed long rods, a structure that is shared among the Complex Associated with Tethering Containing Helical Rods (CATCHRs) proteins from related complexes such as Conserved Oligomeric Golgi complex (COG) and Golgi-Associated Retrograde Protein complex (GARP) [,
,
]. Subunits of these complexes, apart of helical bundles, they usually have a coiled-coil (CC) region at the N-terminal. Sec3 is described as a membrane-anchoring component which serves as a spatial landmark in the plasma membrane for incoming secretory vesicles. Sec3 binds to the C-terminal cytoplasmic domain of GLYT1 (glycine transporter protein 1). Sec3 is recruited to the sites of polarised membrane growth through its interaction with Rho1p, a small GTP-binding protein [].
Diverse DNA binding proteins are known to bind the CCAAT box, a common cis-
acting element found in the promoter and enhancer regions of a large number ofgenes in eukaryotes. Amongst these proteins is one known as the CCAAT-binding
factor (CBF) or nuclear transcription factor Y (NF-Y) []. CBF is a heteromeric transcription factor that consists of two different components both needed for DNA-binding.The HAP protein complex of yeast binds to the upstream activation site of
cytochrome C iso-1 gene (CYC1) as well as other genes involved inmitochondrial electron transport and activates their expression. It also
recognises the sequence CCAAT and is structurally and evolutionary related toCBF.The first subunit of CBF is known as CBF-A or NF-YB in vertebrates, and HAP3 in budding yeast. The second subunit is known as CBF-B or NF-YA in vertebrates and HAP2 in budding yeast. It is a protein of 265 to 350 amino-acid residues which contains a highly conserved region of about 60 residues. This region, called the 'essential core' [
], seems to consist of two subdomains: an N-terminal subunit-association domain and a C-terminal DNA recognition domain.
This entry represents the NF-YA subunit.
The ATP-Binding Cassette (ABC) superfamily forms one of the largest of all protein families with a diversity of physiological functions [
]. Several studies have shown that there is a correlation between the functional characterisation and the phylogenetic classification of the ABC cassette [,
]. More than 50 subfamilies have been described based on a phylogenetic and functional classification [,
,
].Members of this protein family are the ABC transporters of phosphonates. Phosphonates are a class of phosphorus-containing organic compound with a stable direct C-P bond rather than a C-O-P linkage. Phosphonates are widespread among naturally occurring compounds in all kingdoms of wildlife, but only prokaryotic microorganisms are able to cleave this bond. Certain bacteria such as E. coli can use alkylphosphonates as a phosphorus source. A number of bacterial species have operons, typically about 14 genes in size, with genes for ATP-dependent transport of phosphonates, degradation, and regulation of the expression of the system [
,
,
,
,
].This entry also includes transporters of phosphite (an organophosphorous compound with the formula P(OR)
3) and hypophosphite (H
2PO
-2), including the phosphite import ATP-binding protein PxtA and hypophosphite import ATP-binding protein HtxD, both from Pseudomonas stutzeri [
].
Phasins (or granule-associate proteins) are surface proteins found covering Polyhydroxyalkanoate (PHA) storage granules in bacteria. Polyhydroxyalkanoates are linear polyesters produced by bacterial fermentation of sugar or lipids for the purpose of storing carbon and energy, and are accumulated as intracellular granules by many bacteria under unfavorable conditions, enhancing their fitness and stress resistance [
]. The layer of phasins stabilises the granules and prevents coalescence of separated granules in the cytoplasm and nonspecific binding of other proteins to the hydrophobic surfaces of the granules. For example, in Ralstonia eutropha (strain ATCC 17699/H16/DSM 428/Stanier 337) (Cupriavidus necator (strain ATCC 17699 / H16 / DSM 428 / Stanier 337)), the major surface protein of polyhydroxybutyrate (PHB) granules is phasin PhaP1(Reu), which occurs along with three homologues (PhaP2, PhaP3, and PhaP4) that have the capacity to bind to PHB granules but are present at minor levels [,
]. These four phasins lack a highly conserved domain but share homologous hydrophobic regions. Members of this entry are encoded in polyhydroxyalkanoic acid storage system regions in a number of Vibrio species, including Vibrio cholerae V52, Photobacterium profundum SS9, Acinetobacter sp., and Aeromonas hydrophila. Members appear distantly related to the phasin family, see:
and
.
PP2B (calcineurin) is a unique serine/threonine protein phosphatase in its regulation by a second messenger (calcium and calmodulin). PP2B is involved in many biological processes including immune responses, the second messenger cAMP pathway, sodium/potassium ion transport in the nephron, cell cycle progression in lower eukaryotes, cardiac hypertrophy, and memory formation. PP2B is highly conserved from yeast to humans, but is absent from plants. PP2B is a heterodimer consisting of a catalytic subunit (CnA) and a regulatory subunit (CnB); CnB contains four Ca2+ binding motifs referred to as EF hands [
].The PPP (phosphoprotein phosphatase) family, to which PP2B belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP1, PP2A, PP4, PP5, PP6, PP7, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes [
,
]. PPPs belong to the metallophosphatase (MPP) superfamily.
Cytochrome c (CytC) proteins can be defined as electron-transfer proteins having one or several haem c groups, bound to the protein by one or, more generally, two thioether bonds involving sulphydryl groups of cysteine residues. The fifth haem iron ligand is always provided by a histidine
residue. CytC possess a wide range of properties and function in a large number of different redox processes.Ambler [
] recognised four classes of cytC.Class I includes the low-spin soluble CytC of mitochondria and bacteria, with the haem-attachment site towards the N terminus, and the sixth ligand provided by a methionine residue about 40 residues further on towards the C terminus. On the basis of sequence similarity, class I CytC were further subdivided into five classes, IA to IE. Class IC, 'split-alpha-band' Cyt C, possess a widened or split alpha-band of lowered absorptivity. This class includes dihaem Cyt C4 and monohaem Cyt C6 (Cyt C-553) and Cyt C-554.The 3D structures of Chlamydomonas reinhardtii Cyt C6 [
] and Desulfovibrio vulgaris Cyt C-553 [] have been determined. The proteins consist of 4 α-helices; three 'core' helices form a 'basket' around the haem group, with one haem edge exposed to the solvent.
This is the ZF1 (Zinc Finger 1) domain found in Zic family proteins found in Eukaryotes. In humans, there are five members of the Zic family that are involved in human congenital anomalies. One of them, ZIC3, causes X-linked heterotaxy (HTX1), which is a left-right axis disturbance that manifests as variable combinations of heart malformation, altered lung lobation, splenic abnormality and gastrointestinal malrotation. Zic faily proteins contain multiple zinc finger domains (ZFD), which are generally composed of five tandemly repeated C2H2 zinc finger (ZF) motifs. Sequence comparison analysis reveal that this N-terminal ZF (ZF1) domain of the Zic zinc finger domains is unique in that it possesses more amino acid residues (6-38 amino acids) between the two cysteine residues of the C2H2 motif compared to Gli and Glis ZF1s or any of the other ZFs (ZF2-5) in the Gli/Glis/Zic superfamily of proteins. Mutations in cysteine 253 (C253S) or histidine 286 (H286R) in ZIC3 ZF1, which are found in heterotaxy patients, result in extranuclear localization of the mutant ZIC3 protein. Furthermore, mutations in the evolutionarily conserved amino acid residues (C253, W255, C268, H281 and H286) of ZF1 generally impair nuclear localization [
].
Proteins in this entry include low-affinity urea transporters found in the erythrocytes and kidneys of higher organisms. The erythrocyte proteins carry the clinically important Kidd (Jk) blood group antigens which help determine blood type. The two commonest forms are Jk(a) and Jk(b), which arise from a single residue variation at position 280; aspartate in Jk(a) and asparagine in Jk(b) [
]. A much rarer phenotype, Jk(null), arises when the protein is not expressed on the erythrocyte surface, and is linked to a urine-concentrating defect []. The Kidd blood group is clinically significant as Jk antibodies can cause acute transfusion reactions and haemolytic disease of the newborn (HDN), where the mother's body creates antibodies against the foetal blood cells. HDN associated with Jk antibodies is generally mild, but fatal cases can occur [].The bacterial proteins in this entry also appear to be involved in urea transport, promoting its entry into the cell [
]. This uptake of urea can be advantageous for bacteria as its hydrolysis by urease generates ammonium which is an efficient source of nitrogen and, through its buffering capacity, can also provide resistance to acidic conditions.
Cytochromes c (cytC) can be defined as electron-transfer proteins having
one or several haem c groups, bound to the protein by one or, more generally, two thioether bonds involving sulphydryl groups of cysteine
residues. The fifth haem iron ligand is always provided by a histidine residue. CytC possess a wide range of properties and function in a large
number of different redox processes. Ambler [] recognised four classes of cytC. Class II includes the
high-spin cytC' and a number of low-spin cytochromes, e.g. cyt c-556. The haem-attachment site is close to the C terminus. The cytC' are capable
of binding such ligands as CO, NO or CN(-), albeit with rate and equilibriumconstants 100 to 1,000,000-fold smaller than other high-spin haemoproteins
[]. This, coupled with its relatively low redox potential, makes itunlikely that cytC' is a terminal oxidase. Thus cytC' probably functions
as an electron transfer protein []. The 3D structures of a number of cytC' have been determined. The molecule
usually exists as a dimer, each monomer folding as a four-α-helix bundleincorporating a covalently-bound haem group at the core [
]. The Chromatium vinosum cytC' exhibits dimer dissociation upon ligand binding [].
Cytochromes c (cytC) can be defined as electron-transfer proteins having
one or several haem c groups, bound to the protein by one or, more generally, two thioether bonds involving sulphydryl groups of cysteine
residues. The fifth haem iron ligand is always provided by a histidine residue. CytC possess a wide range of properties and function in a large
number of different redox processes. Ambler [] recognised four classes of cytC. Class II includes the high-spin cytC' and a number of low-spin cytochromes, e.g. cyt c-556. The haem-attachment site is close to the C terminus. The cytC' are capable of binding such ligands as CO, NO or CN(-), albeit with rate and equilibrium constants 100 to 1,000,000-fold smaller than other high-spin haemoproteins [
]. This, coupled with its relatively low redox potential, makes it unlikely that cytC' is a terminal oxidase. Thus cytC' probably functions as an electron transfer protein []. The 3D structures of a number of cytC' have been determined. The molecule
usually exists as a dimer, each monomer folding as a four-α-helix bundleincorporating a covalently-bound haem group at the core [
]. The Chromatium vinosum cytC' exhibits dimer dissociation upon ligand binding [].
HTLV-1 encodes two proteins that have been reported to drive oncogenesis: Tax and HTLV-1 basic leucine zipper (bZIP) factor (HBZ). HBZ has been shown to enhance viral infectivity and persistence, and facilitates proliferation of HTLV-1-infected lymphocytes [
]. It has also been shown to attenuates DSB (double-stranded DNA breaks) repair by nonhomologous end joining (NHEJ), in a manner dependent upon the bZIP domain []. HBZ has been shown to negatively regulate basal and Tax-dependent HTLV-1 transcription through its ability to interact with specific basic-leucine zipper (bZIP) proteins. HBZ has been shown to reduce HTLV-1 transcription and virion production. The protein interacts with CREB in vivo and directly in vitro via the bZIP domain of each protein; CREM-Ia and ATF-1 also interact with HBZ-bZIP. The interaction between CREB and HBZ prevents CREB binding to the viral CRE elements in vitro and in vivo, suggesting that the reduction in HTLV-1 transcription by HBZ partly results from the the loss of CREB at the promoter. It has also been shown that HBZ displaces CREB from a cellular CRE, suggesting that HBZ may de-regulate CREB-dependent cellular gene expression [
].
This entry represents the C2 domain found in cytosolic phospholipase A2 (cPLA2), which hydrolyzes arachidonyl phospholipids in the sn-2 position releasing arachidonic acid. The cooperative binding of two Ca(2+) ions to the C2 domain of cPLA2-alpha induces docking to phosphatidylcholine (PC) membranes [
]. This domain have a type-II C2 domain topology. C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions [
,
].
RNA-directed DNA polymerase (reverse transcriptase), msDNA
Type:
Family
Description:
The use of an RNA template to produce DNA, for integration into the host genome and exploitation of a host cell, is a strategy employed in the replication of retroid elements, such as the retroviruses and bacterial retrons. The enzyme catalysing polymerisation is an RNA-directed DNA-polymerase, or reverse trancriptase (RT) (). Reverse transcriptase occurs in a variety of mobile elements, including retrotransposons, retroviruses, group II introns, bacterial msDNAs, hepadnaviruses, and caulimoviruses. The enzymatic reaction leads to the production of a unique RNA-DNA complex called msDNA (multicopy single-stranded DNA) in which a single-stranded DNA branches out from an RNA molecule via a 2',5'-phosphodiester linkage [
].Retroviral reverse transcriptase is synthesised as part of the POL polyprotein that contains; an aspartyl protease, a reverse transcriptase, RNase H and integrase. POL polyprotein undergoes specific enzymatic cleavage to yield the mature proteins. The discovery of retroelements in the prokaryotes raises intriguing questions concerning their roles in bacteria and the origin and evolution of reverse transcriptases and whether the bacterial reverse transcriptases are older than eukaryotic reverse transcriptases [
].This protein family includes a number of bacterial reverse transcriptases, including Retron Ec73 reverse transcriptase from Escherichia coli and Trt from Bacillus stearothermophilus (
).
Cytochromes c (cytC) can be defined as electron-transfer proteins having
one or several haem c groups, bound to the protein by one or, more generally, two thioether bonds involving sulphydryl groups of cysteine
residues. The fifth haem iron ligand is always provided by a histidine residue. CytC possess a wide range of properties and function in a large
number of different redox processes. Ambler [] recognised four classes of cytC. Class II includes the
high-spin cytC' and a number of low-spin cytochromes, e.g. cyt c-556. The haem-attachment site is close to the C terminus. The cytC' are capable
of binding such ligands as CO, NO or CN(-), albeit with rate and equilibriumconstants 100 to 1,000,000-fold smaller than other high-spin haemoproteins
[]. This, coupled with its relatively low redox potential, makes itunlikely that cytC' is a terminal oxidase. Thus cytC' probably functions
as an electron transfer protein []. The 3D structures of a number of cytC' have been determined. The molecule
usually exists as a dimer, each monomer folding as a four-α-helix bundleincorporating a covalently-bound haem group at the core [
]. The Chromatium vinosum cytC' exhibits dimer dissociation upon ligand binding [].
This domain is found predominantly in fungal members of the peptidase family S8 (subtilisin) [
]. These proteins contain an additional domain inserted within the subtilisin domain known as a PA (protease-associated) domain. The only characterized member is the PoSI peptidase (MEROPS identifier S08.139) from the oyster mushroom (Pleurotus ostreatus). The peptidase is a two-chain, secreted glycoprotein probably involved in the activation of other peptidases secreted by the mushroom [
].The subtilisin family is one of the largest serine peptidase families characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence [
]. It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses []. The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase [,
]. Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity [,
]. Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein [].
RIP kinases serve as essential sensors of cellular stress. Vertebrates contain several types containing a homologous N-terminal kinase domain and varying C-terminal domains [
,
]. RIP1 harbours a C-terminal Death domain (DD), which binds death receptors (DRs) including TNF receptor 1, Fas, TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1), and TRAILR2. It also interacts with other DD-containing adaptor proteins such as TRADD and FADD. RIP1 plays a crucial role in determining a cell's fate, between survival or death, following exposure to stress signals. It is important in the signaling of NF-kappaB and MAPKs, and it links DR-associated signaling to reactive oxygen species (ROS) production. Abnormal RIP1 function may result in ROS accumulation affecting inflammatory responses, innate immunity, stress responses, and cell survival [,
]. DDs (Death domains) are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes [
,
].
