This is a small family of large proteins (~1300-1500 residues) containing one copy of the metallophosphoesterase domain. With the exception of glutamine replacing one metal-binding histidine, they possess the motifs characteristic of a variety of enzymatically active phosphoesterases [
], including acid and alkaline phosphatases, phosphoprotein phosphatases, 5'-nucleotidase, bis(5'-nucleosyl)-tetraphosphatase (symmetrical), sphingomyelin phosphodiesterase, 2',3'-cylic-nucleotide 2'-phosphodiesterase, and the 3',5'-nucleotide phosphodiesterase CpdA.Although the sequences within this family are well-conserved throughout most of their lengths, with the exception of the portion of the protein containing the metallophosphoesterase domain (about one-sixth of the whole), they have little similarity to any other type of characterised protein.
Copines are a widely distributed class of Ca2+-dependent lipid-binding proteins. Most have a characteristic domain structure: two C2 domains in the N-terminal region and a von Willebrand A (VWA) domain in the C-terminal region. They are potentially involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth [
,
]. In plants, they are known as BONZAI proteins []. The copine family in plants may have effects in promoting growth and development in addition to repressing cell death [,
]. Caenorhabditis elegans copine, also known as Nra1, is Involved in nicotinic acetylcholine receptor (nAChR)-mediated sensitivity to nicotine and levamisole [].
This entry represents a group of RING finger-containing proteins, including RNF123/RSPRY1 from humans and RKP from Arabidopsis.RNF123 is the catalytic subunit of the KPC complex that acts as E3 ubiquitin-protein ligase. It also functions as an inhibitor of innate antiviral signalling mediated by DDX58 and IFIH1 independently of its E3 ligase activity [
]. The role of RSPRY1 (RING finger and SPRY domain-containing protein 1) is not known, but it may have a role in bone development. Mutations in RSPRY1 cause skeletal dysplasia [].RKP is an E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of KRP1 and KRP2 [
,
].
Neuromodulin (also known as GAP-43, pp46, B-50, F1, and P-57) [
] is an axonalmembrane protein associated with nerve growth. It is a major component of the
motile growth cones that form the tips of elongating axons. Neuromodulin is anhydrophilic protein of 210 to 240 amino acid residues, which binds calmodulin
and inhibits phosphatidylinositol phosphate kinase (PIP kinase). It isphosphorylated by protein kinase C, and regulates the binding of GTP to G(0)
[]. Neuromodulin contains an IQ motif.This entry represents the N-terminal extremity containing two cysteine residues which are palmitoylated and are responsible for the attachment of the protein to the membrane.
FYVE domain protein required for endosomal sorting 1 (FREE1), also known as FYVE domain-containing protein 1 (FYVE1) is a component of the endosomal sorting complex required for transport (ESCRT), involved in multivesicular body (MVB) protein sorting and plant growth [
,
,
]. It negatively regulates salt stress tolerance via a negative feedback loop involving abscisic acid (ABA) signaling pathway []. The the N-terminal domain of FREE1 is required for the interaction with the Ubiquitin-binding ESCRT-I subunit proteins VPS23A and B, the FYVE domain is required for phosphatidylinositol-3-phosphate (PI3P) binding, and the C-terminal domain for the binding to ubiquitin [
,
].
This entry represents a domain of unknown function found in the Telomerase protein component 1 (TEP1) from in animals. It contains an homology region to the Telomerase associated protein from Tetrahymena p80 [
].TEP1 is a component of the telomerase ribonucleoprotein complex and is thought to be responsible for catalysing the addition of new telomeres to chromosomes. TEP1 is also a component of the vault particle, a cytoplasmic ribonucleoprotein complex, in which it is required for vault RNA stability and its association with the vault particle [
]. This domain is localised between the TROVE () and DUF4062 (
) domains.
SseC is a secreted protein that forms a complex together with SecB and SecD on the surface of Salmonella typhimurium. All these proteins are secreted by the type III secretion system [
]. Many mucosal pathogens use type III secretion systems for the injection of effector proteins into target cells. SecB, SseC and SecD are inserted into the target cell membrane. where they form a small pore or translocon [,
]. In addition to SseC, this family includes the bacterial secreted proteins PopB, PepB, YopB and EspD which are thought to be directly involved in pore formation, and type III secretion system translocon.
This is an NSD-specific Cys-His rich region (C5HCH) domain. Proteins containing this domain include NSD (nuclear receptor SET domain-containing) proteins. This domain is located on the C-terminal of NSD1, 2 and 3 proteins. C5HCH domain lies adjacent to the fifth plant homeodomain (PHD5). The PHD5-C5HCH module of NSD3 (PHD5-C5HCHNSD3) recognises the H3 N-terminal peptide containing unmodified K4 and trimethylated K9. Moreover, it has been reported that the PHD5-C5HCH module of NSD1 (PHD5-C5HCH) was the sole region required for tight binding of the NUP98-NSD1 fusion protein to the HoxA9 gene promoter, implicating that PHD5-C5HCH might have chromatin targeting ability [
].
This entry represents seminal plasma proteins, including PDC-109, BSP-A3, HSP-1 and pB1. On ejaculation, sperm becomes coated with these proteins, which are secreted by male accessory sex glands. These proteins play a role in forming an oviductal sperm reservoir by enabling sperm to bind to oviductal epithelium [
]. PDC-109 could enhance the fertilising capacity of spermatozoa upon interaction with heparin-like glycosaminoglycans present in the female genital tract []. PDC-109 and BSP-A3 exert both stimulatory and inhibitory actions on the release of pituitary gonadotropins. Protein pB1 may form a complex with spermadhesin AQN-1 which possesses phosphorylcholine-binding activity [].
The MKRN protein family includes the ribonucleoproteins that are characterised by a variety of zinc-finger motifs, including typical arrays of one to four C3H1-type zinc fingers and a C3HC4-type RING-HC finger. Another motif rich in Cys and His residues (CH), with so far unknown function, is also generally present in MKRN proteins. MKRN proteins may have E3 ubiquitin ligase activity [
,
]. At least four makorin genes exist in vertebrates [].Makorin 3 was first identified in the Prader-Willi syndrome critical region in the human genome, but has no obvious role in the disease [
].
Lipoic acid is an essential cofactor of the alpha-ketoacid dehydrogenase complexes and the glycine cleavage system. It is covalently attached to a specific lysine residue of the subunit of the complexes.In mammals, covalent attachment of lipoic acid to the proteins occurs in two successive reactions. First, lipoic acid is activated to lipoyl-AMP by lipoate-activating enzyme, and then the lipoyl moiety is transferred to apoproteins by the action of lipoyltransferase [
,
]. In contrast, in Escherichia coli, lipoate-protein ligase A catalyses both the activation and the transfer of lipoate []. This entry includes lipoyltransferases and lipoate-protein ligases.
Asparagine-linked glycosylation is a post-translational modification of proteins containing the conserved sequence motif Asn-X-Ser/Thr. The attachment of oligosaccharides is implicated in diverse processes such as protein folding and quality control, organism development or host-pathogen interactions. The reaction is catalysed by oligosaccharyltransferase (OST), a membrane protein complex located in the endoplasmic reticulum. The central, catalytic enzyme of OST is the STT3 subunit, which has homologues in bacteria and archaea. Structural analysis of a bacterial OST, undecaprenyl-diphosphooligosaccharide protein glycotransferase (PglB,
), revealed two domains: a transmembrane domain and a periplasmic domain. This entry represents the C-terminal periplasmic β-barrel domain [
].
This group represents Rev protein from Ovine/caprine lentiviruses [
]. The Rev protein escorts unspliced or incompletely spliced viral pre-mRNAs (late transcripts) out of the nucleus of infected cells. These pre-mRNAs carry a recognition sequence called Rev responsive element (RRE) located in the env gene, that is not present in fully spliced viral mRNAs (early transcripts) []. This function is essential since most viral proteins are translated from unspliced or partially spliced pre-mRNAs, which cannot exit the nucleus by the pathway used by fully processed cellular mRNAs. Rev protein is a homomultimer when bound to RRE, its multimeric assembly being essential for activity.
This is an immunoglobulin domain which can be found in Interleukin-1 receptors [
] and Interleukin 1 receptor accessory proteins (IL-1RAcP). IL-1RAcP is a member of the Ig superfamily and has a limited homology throughout the protein to both Type I and Type II IL-1 receptors. IL-1RAcP is a transmembrane protein required for IL-1 signal transduction [
]. It increases the binding affinity of the recombinant Type I IL-1R for IL-1 beta when the two receptor proteins are co-expressed []. It has been suggested to play a role in the formation of the active receptor complex [].
This entry includes FMP27 (also known as Hob1), C3H5.09c from S.pombe, Hobbit from fruit fly and BLTP2 from human (also known as KIAA0100), which are known as Hob proteins. They are tube-forming lipid transport proteins which bind to phosphatidylinositols and affects phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) distribution [
,
,
]. They belong to the repeating β-groove (RBG) superfamily together with VPS13, ATG2, SHIP164, Csf1/BLTP1 proteins, which are all conserved lipid transfer proteins containing long hydrophobic grooves [,
]. They all share the same structure consisting of multiple repeating modules comprising five β-sheets followed by a loop.This entry represents the N-terminal of FMP27 and BLTP2.
SR-25, otherwise known as ADP-ribosylation factor-like factor 6-interacting protein 4, is expressed in virtually all tissue types. At the N terminus there is a repeat of serine-arginine (SR repeat), and towards the middle of the protein there are clusters of both serines and of basic amino acids. The presence of many nuclear localisation signals strongly implies that this is a nuclear protein that may contribute to RNA splicing [
]. SR-25 is also implicated, along with heat-shock-protein-27, as a mediator in the Rac1 (GTPase ras-related C3 botulinum toxin substrate 1; also see ) signalling pathway [
].
This highly conserved motif is thought to be a transmembrane helix that binds to transient receptor potential (TRP) calcium channel. It is found in proline-rich protein 24 (PRR24) and in InaF proteins. It is known that proline-rich proteins inactivate tannins found in food compounds, and it is thought that PRR24 does too. This is important since tannins often inhibit the uptake of iron [
]. InaF is a protein required for TRP calcium channel function in Drosophila [,
]. TRP-related channels have been suggested to mediate "store-operated"calcium entry, important for Ca2+ homeostasis in a wide variety of cell types [
].
Thiazole/oxazole-forming peptide maturase, SagC family component
Type:
Family
Description:
Members of this protein family include enzymes related to SagC, a protein involved in thiazole/oxazole cyclodehydration modifications during biosynthesis of streptolysin S in Streptococcus pyogenes from the protoxin polypeptide (product of the sagA gene). Recent evidence suggests that the YcaO/SagD-like component, not this component, performs an ATP-dependent cyclodehydration [
]. This protein family serves as a marker for widely distributed prokaryotic systems for making a general class of heterocycle-containing bacteriocins []. Note that this model does not find all possible examples of bacteriocin biosynthesis cyclodehydratases, an in particular misses the E. coli plasmid protein McbB of microcin B17 biosynthesis.
Many bacterial species swim actively by means of flagella. The flagella
organelle is made of three parts: the basal body, the hook and the filament.The basal body consists of four rings (L,P,S, and M) mounted on a central rod [
].In Salmonella typhimurium and related organisms the rod has been shown to
consist of four different, yet evolutionary related proteins: in the distalportion of the rod there are about 26 subunits of protein flgG and in the
proximal portion there are about six subunits each of proteins flgB, flgC, andflgF.
These four proteins contain a highly conservedasparagine-rich domain at their N terminus.
UBL4A (also known as GdX) is a ubiquitously expressed ubiquitin-like (Ubl) protein that forms a complex with partner proteins and participates in the protein processing through endoplasmic reticulum (ER), acting as a chaperone. As a key component of the BCL2-associated athanogene 6 (BAG6) chaperone complex, UBL4A plays a role in mediating DNA damage signaling and cell death [
,
]. UBL4A also regulates insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching []. Moreover, UBL4A specifically stabilises the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis [].This is the ubiquitin-like domain of UBL4A and related proteins.
Tubulin proteostasis is regulated by a group of molecular chaperones termed tubulin cofactors (TBC). This entry represents TBCE (tubulin-specific chaperone E), which is an alpha-tubulin binding protein that, together with Arl2 and cofactors D (TBCD), A (TBCA or p14), B (TBCB) and C (TBCC), participate in tubulin biogenesis [
]. TBCE contains an N-terminal cytoskeleton-associated protein with glycine-rich segment (CAP-Gly) domain, a leucine-rich repeat protein-protein interaction domain followed by leucine-rich repeat (LRR) domains, and a C-terminal ubiquitin-like (Ubl) domain [].Mutations in TBCE gene cause the Kenny-Caffey/Sanjad-Sakati syndrome, characterised by hypoparathyroidism, mental retardation and facial dysmorphism [
].
Protrudin is a membrane protein that regulates polarized vesicular trafficking in neurons. It interacts with KIF5, a motor protein that mediates anterograde vesicular transport in neurons [
]. Protrudin contains a Rab11-binding domain, a FYVE (lipid-binding) domain, and a short sequence motif designated FFAT (two phenylalanines in an acidic tract) between the Rab11 binding domain and the FYVE domain. The FFAT motif mediates the interaction of protrudin with vesicle-associated membrane protein-associated protein (VAP) as well as with Kif5A. Protrudin has been linked to Hereditary spastic paraplegia (HSP), an inherited neurological disorders characterised by progressive lower-limb spasticity and weakness. [].
Cren7 is a chromatin protein found in Crenarchaeota and has a higher affinity for double-stranded DNA than for single-stranded DNA. The protein contains negative DNA supercoils and is associated with genomic DNA in vivo. Cren7 interacts with duplex DNA through a β-sheet and a long flexible loop. It is binding to double-stranded DNA without sequence specificity [
]. There is approximately 1 Cren7 molecule for 12 bp of DNA. The function of Cren7 has not been completely determined but it is thought that the protein may have a role similar to that of archaeal proteins in Euryarchaea [].
This domain is found in proteins from Metazoa. Some proteins also carry kinesin-motor domains at their N terminus (
).
Proteins containing this domain include the coiled-coil domain-containing protein 78 (CCDC78), which is a component of the deuterosome, a structure that promotes de novo centriole amplification in multiciliated cells that can generate more than 100 centrioles [
]. CCDC78 does not have the kinesin-motor domain. Mutations in CCDC78 genes cause Myopathy, centronuclear, 4 (CNM4), which is a congenital muscle disorder characterised by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles [].
This family of proteins is a highly specific ubiquitin iso-peptidase that removes ubiquitin from proteins [
]. The modification of cellular proteins by ubiquitin (Ub) is an important event that underlies protein stability and function in eukaryotes, as it is a dynamic and reversible process. Otubain carries several key conserved domains: (i) the OTU (ovarian tumour domain) in which there is an active cysteine protease triad (ii) a nuclear localisation signal, (iii) a Ub interaction motif (UIM)-like motif phi-xx-A-xxxs-xx-Ac (where phi indicates an aromatic amino acid, x indicates any amino acid and Ac indicates an acidic amino acid), (iv) a Ub-associated (UBA)-like domain and (v) the LxxLL motif [].
Eukaryotic translation initiation factor 4E (eIF-4E) [
] is a protein thatbinds to the cap structure of eukaryotic cellular mRNAs. eIF-4E recognises and binds
the 7-methylguanosine-containing (m7Gppp) cap during an early step in the initiationof protein synthesis and facilitates ribosome binding to a mRNA by inducing the unwinding
of its secondary structures. A tryptophan in the central part of the sequence of humaneIF-4E seems to be implicated in cap-binding [
].This entry includes a group of eIF4E-like protein. These proteins consist of a curved eight-stranded antiparallel β-sheet, decorated with three helices on the convex face and three smaller helices inserted in connecting loops [
].
The lysosomal degradation of several sphingolipids requires the presence of four small glycoproteins called saposins, generated by proteolytic processing of a common precursor, prosaposin [
]. Saposins have three conserved disulphide bridges, and display a 5-helical, closed, folded leaf topology. Other proteins have been shown to have structures that closely resemble saposin, such as the antimicrobial peptides NK-lysin and granulysin [,
]. Some proteins contain saposin-like domains, such as prophytepsin, an acid protease from plants, and J3-crystallin, an eye-lens protein from jellyfish, both of which contain circularly permuted saposin motifs called swaposin [,
]. In some saposins and saposin-like domains, lipid-binding can promote conformational changes and oligomerization.
This entry contains a number of protein families with apparently unrelated functions. The yeast YAP binding proteins are stress response and redox homeostasis proteins, induced by hydrogen peroxide or induced in response to alkylating agent methyl methanesulphonate (MMS) [
,
]. Aberrant root formation protein 4 (ALF4) of Arabidopsis thaliana (Mouse-ear cress),is required for the initiation of lateral roots independent from auxin signalling. It may also function in maintaining the pericycle in the mitotically competent state needed for lateral root formation []. Glomulin (FAP68) is essential for normal development of the vasculature and may represent a naturally occurring ligand of the immunophilins FKBP59 and FKBP12 [,
].
This family contains Dephospho-coenzyme A kinase (DPCK,
), which catalyzes the final step in dephosphocoenzyme A (dCoA) biosynthesis, the phosphorylation of the 3'-hydroxyl group of ribose using ATP as a phosphate donor.
The crystal structures of a number of the proteins in this entry have been determined, including the structure of the protein from Haemophilus influenzae to 2.0-A resolution in a comlex with ATP. The protein consists of three domains: the nucleotide-binding domain with a five-stranded parallel β-sheet, the substrate-binding α-helical domain, and the lid domain formed by a pair of α-helices; the overall topology of the protein resembles the structures of other nucleotide kinases [
].
This entry include proteins from the FYV7 and the TAP26 families [
]. FYV7 is involved in the processing of 20S pre-rRNA during the maturation of SSU-rRNA from tricistronic RNA transcripts (SSU-rRNA, 5.8S rRNA, LSU-rRNA). The SSU (small subunit) processome is required for production of the small ribosomal subunit RNA, the 18S rRNA [
]. Fyv7 may also be required for survival upon K1 Killer toxin exposure.Thyroid transcription factor 1-associated protein 26 (TAP26, also known as BR22) is a component of the transcription complexes of the pulmonary surfactant-associated protein-B (SFTPB) and -C (SFTPC). It enhances homeobox protein Nkx-2.1-activated SFTPB and SFTPC promoter activities [
,
].
This domain is found in the eukaryotic family defective in cullin neddylation, which includes DCN1 and DCN1-like proteins. Proteins of the DCN family may contribute to neddylation of cullin components of SCF-type E3 ubiquitin ligase complexes, which are multi-protein complexes required for polyubiquitination and subsequent degradation of target proteins by the 26S proteasome [
,
].The structure of this domain is composed entirely of alpha helices [
,
]. It has been referred to as potentiating neddylation domain (PONY) and can be found in association with an N-terminal UBA domain. The PONY domain contains a cullin-binding surface within its C-terminal region and is sufficient to promote neddylation [,
].
The ~60-residue RAP (an acronym for RNA-binding domain abundant in Apicomplexans) domain is found in various proteins in eukaryotes. It is particularly abundant in apicomplexans and might mediate a range of cellular functions through its potential interactions with RNA [
].The RAP domain consists of multiple blocks of charged and aromatics residues and is predicted to be composed of α-helical and β-strand structures. Two predicted loop regions that are dominated by glycine and tryptophan residues are found before and after the central β-sheet [
].Some proteins known to contain a RAP domain are listed below: Human hypothetical protein MGC5297, Mammalian FAST kinase domain-containing proteins (FASTKDs), Chlamydomonas reinhardtii chloroplastic trans-splicing factor Raa3.
Fibrillarin is a component of a nucleolar small nuclear ribonucleoprotein (SnRNP), functioning
in vivoin ribosomal RNA processing [,
]. It is associated with U3, U8 and U13 small nuclearRNAs in mammals [
] and is similar to the yeast NOP1 protein []. Fibrillarin has awell conserved sequence of around 320 amino acids, and contains 3 domains, an N-terminal Gly/Arg-rich
region; a central domain resembling other RNA-binding proteins and containing an RNP-2-like consensussequence; and a C-terminal α-helical domain. An evolutionarily related pre-rRNA processing protein,
which lacks the Gly/Arg-rich domain, has been found in various archaebacteria.The signature pattern for this entry encompasses the RNP-2 like octapeptide sequence.
Knottins are small proteins characterised by a cystine-knot [
]. They constitute a large family of structurally related peptides with diverse biological functions, including inhibitors, anti-microbial peptides and toxins [].The scorpion toxin-like domain is found in a subgroup of metazoan knottins mainly from the arthropoda, which include the antibacterial defensins [
] and the scorpion alpha and beta-neurotoxins [,
]. The plant sequences include members of the gamma-thionin family, which are plant defensins that have no antifungal activity. Other members are insect alpha-amylase inhibitors, cysteine-rich antifungal proteins and proteins annotated as proteinase inhibitors; those that are characterised belong to MEROPS inhibitor family I18, clan I.
2H-phosphodiesterase-like, Domain of unknown function DUF1868
Type:
Domain
Description:
This presumed domain is found in a group of 2H-phosphodiesterases predominantly from bacteria. Its presence in a large eukaryotic DNA virus represents a potential case of horizontal transfer from a bacterial source into a virus. Several proteins of bacterial origin have been noticed in the insect viruses and these appear to have been acquired from endo-symbiotic or parasitic bacteria that share the same host cells with the viruses. Presence of 2H proteins in the proteomes of large DNA viruses (e.g. T4 57B protein and the Fowl-pox virus FPV025) may point to some role for these proteins in regulating the viral tRNA metabolism [
].
This entry includes a group of transmembrane proteins, including MgtC, SapB, SrpB and YhiD from bacteria. The MgtC protein is found in an operon with the Mg2+ transporter protein MgtB. However, MgtC is not a Mg2+ transporter [
,
]. The expression of MgtC is a virulence factor required for growth in low Mg2+ medium and for intramacrophage survival []. MgtC may be involved in regulating membrane potential by activating Na+/K+-ATPase [,
]. YhiD from E. coli is an integral membrane protein related to MgtC. It has been suggested to be an essential component for the Mg2+ uptake system in E. coli [
].
This entry consists of Pseudomonas aeruginosa PA3087 and related proteins. PA3087 is an uncharacterized protein from Pseudomonas aeruginosa with a metallophosphatase domain that belongs to the phosphoprotein phosphatase (PPP) family.The PPP family also includes: PP1, PP2A, PP2B (calcineurin), 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 [
,
].
A family of bacterial proteins has been described which groups transcriptional repressors, sugar kinases and yet uncharacterised open reading frames [
]. This family, known as ROK (Repressor, ORF, Kinase) includes the xylose operon repressor, xylR, from Bacillus subtilis, Lactobacillus pentosus and Staphylococcus xylosus; N-acetylglucosamine repressor, nagC, from Escherichia coli; glucokinase from Streptomyces coelicolor; fructokinase
from Pediococcus pentosaceus, Streptococcus mutans and Zymomonas mobilis; allokinase
and mlc from E. coli; and E. coli hypothetical proteins yajF and yhcI and the corresponding Haemophilus influenzae proteins. The repressor proteins (xylR and nagC) from this family possess an N-terminal region not present in the sugar kinases and which contains an helix-turn-helix DNA-binding motif.
This entry represents the calcium-binding type 3 (T3) repeats found in extracellular calcium-binding multifunctional proteins, thrombospondins (TSPs). The T3 repeats lack secondary structure and are organised around a core of calcium ions; two DxDxDGxxDxxD motifs per repeat each encapsulate two calcium ions in a novel arrangement [
]. TSP type-3 repeat can be found in the following proteins:
Cartilage oligomeric matrix protein: may play a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin [
].Outer membrane porin F from bacteria [
]. Alpha-agarase: hydrolyses agarose, agarohexaose, neoagarohexaose and porphyran [
,
].
YaaA has a single S4 domain (
). It may be a ribosome maturation protein that its overexpression can restore both the growth and the sporulation defects caused by mutation of rplB, encoding ribosomal protein L2 [
].The S4 domain may bind RNA. Members of this protein are found almost exclusively in the Firmicutes, and almost invariably just a few nucleotides upstream of the gene for the DNA replication and repair protein RecF. The few members that are not near recF are found instead near dnaA and/or dnaN, the usual neighbours of recF, near the origin of replication. The conserved location suggests a possible role in replication in the Firmicutes lineage.
This superfamily represents the C-terminal domain of RFXAP (regulatory factor X-associated protein) that binds to RFXANK [
,
], the ankyrin-repeat regulatory factor X protein. RFXAP is part of the RFX complex, mutants of either RFXAP or RFXANK protein fail to bind to each other. RFX5 binds only to the RFXANK-RFXAP scaffold and not to either protein alone, and neither the scaffold nor RFX5 alone can bind DNA. The binding of the RFXANK-RFXAP scaffold to RFX5 leads to a conformational change in the latter that exposes the DNA-binding domain of RFX5. The DNA-binding domain of RFX5 anchors the RFX complex to MHC class II X and S promoter boxes [
].
ABC-type glycine betaine transport system, substrate-binding domain
Type:
Domain
Description:
This domain is a part of a high affinity multicomponent binding-protein-dependent transport system involved in bacterial osmoregulation. This domain is often fused to the permease component of the transporter complex. It is often found in integral membrane proteins or proteins predicted to be attached to the membrane by a lipid anchor. Glycine betaine is involved in protection from high osmolarity environments for example in Bacillus subtilis [
]. OpuBC is closely related and involved in choline transport. Choline is necessary for the biosynthesis of glycine betaine []. L-carnitine is important for osmoregulation in Listeria monocytogenes. This domain is found also in proteins binding l-proline (ProX), histidine (HisX) and taurine (TauA).
Many peptide-modifying radical SAM enzymes have two 4Fe4S-binding regions, an N-terminal one recognised by
and a C-terminal one recognised by
. Members of this protein family occur in cassettes with such a radical SAM family
and with a peptide modification target
. Surprisingly, members of this family show full-length homology to each other, with several scoring at least borderline hits to both
and
, and yet differ in the presence/absence of a signature CX(3)CX(2)CX(9)C motif. Instead, members are best-conserved in the
-like C-terminal region. Therefore, this protein family is designated a quasi-radical-SAM protein, which likely works in partnership with a
family protein [
].
This superfamily includes large ribosomal subunit protein L21 and mitochondrial ribosomal subunit from yeast L49 (Mrpl49). In S. pombe, the putative mitochondrial ribosomal protein bL21 (Mrpl49) is fused to aconitase [
]. L21 has a small β-barrel-like domain that is connected to an extended loop [].In Escherichia coli, L21 is known to bind to the 23S rRNA in the presence of L20. It belongs to a family of ribosomal proteins which, on the basis of sequence similarities, groups:
Bacterial L21.Marchantia polymorpha chloroplast L21.Cyanelle L21.Plant chloroplast L21 (nuclear-encoded).Bacterial L21 is a protein of about 100 amino-acid residues, the mature form of the spinach chloroplast L21 has 200 residues.
This entry includes TraB/PrgY proteins which have been identified in gut bacterium Enterococcus faecalis, and are induced by pheromones. This induction rends the host bacterium insensitive to self-induction by its own pheromones, and prevents the transfer of the pheromone-inducible conjugative plasmids to bacteria that already contain it [
,
,
]. TraB proteins belong to the Tiki-like superfamily, and based on its homology to Tiki, it has been proposed that TraB acts as a protease in the inactivation of mating pheromone, cleaving at the amino-terminus [
,
,
].This family includes TraB domain-containing proteins from mammals, whose function is not clear, and TraB-like proteins from bacteria.
SRSF11, also known as SRp54 or p54, belongs to the SR proteins family. It is involved in bridge-complex formation and splicing by mediating protein-protein interactions across either introns or exons. SRSF11 has been identified as a tau exon 10 splicing repressor. It interacts with a purine-rich element in exon 10, and suppresses exon 10 inclusion by antagonizing Tra2beta, an SR-domain-containing protein that enhances exon 10 inclusion [
]. SRSF11 has also been shown to associate with active telomerase through the interaction with TERC and directs it to nuclear speckles specifically during S phase []. This entry represents the RNA recognition motif (RRM) domain of SRSF11.
STKs (serine/threonine-protein kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TSSK (testis-specific serine kinase) proteins are almost exclusively expressed postmeiotically in the testis and play important roles in spermatogenesis and/or spermiogenesis. There are five mammalian TSSK proteins which show differences in their localization and timing of expression [
]. TSSK6, also called SSTK, is expressed at the head of elongated sperm. It can phosphorylate histones and associate with heat shock protens HSP90 and HSC70. Male mice deficient in TSSK6 are infertile, showing spermatogenic impairment including reduced sperm counts, impaired DNA condensation, abnormal morphology and decreased motility rates [,
].
The MOB kinase activator superfamily includes MOB1, an essential Saccharomyces cerevisiae protein, identified from a two-hybrid screen, that binds Mps1p, a protein kinase essential for spindle pole body duplication and mitotic checkpoint regulation. Conditional alleles of MOB1 cause a late nuclear division arrest at restrictive temperature [
]. This superfamily also includes the MOB-like protein phocein, an intracellular protein that interacts with striatin and may play a role in membrane trafficking []. Structurally, domains in this superfamily have a bromodomain-like fold, which consists of four helices arranged as a bundle with a minor mirror variant of up-and-down topology; they also contain a zinc-binding site.
This entry represents the C-terminal BACK (BTB and C-terminal Kelch) domain of speckle-type POZ protein (SPOP, also known as HIB homologue 1 or Roadkill homologue 1). This domain contains a pair of α-helices which seem to be conserved among Cul3 adaptors [
].SPOP is an adaptor protein that forms a complex with Cul3, cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, and is involved in ubiquitination of BMI1, H2AFY, and the death-associated protein 6 (DAXX) [
]. The C-terminal BACK domain of SPOP, may be involved in oligomer formation and in recruiting Cul3 (together with the adjacent BTB domain), whereas the N-terminal MATH domain recruits substrates [,
].
Proteins containing this domain include kintoun, Saccharomyces cerevisiae PIH1 (protein interacting with Hsp90 1, also known as Nop17) and PIH1 domain-containing proteins. Kintoun is required for cytoplasmic pre-assembly of axonemal dyneins, thereby playing a central role in motility in cilia and flagella. It involved in pre-assembly of dynein arm complexes in the cytoplasm before intraflagellar transport loads them for the ciliary compartment [
].PIH1 is a component of the conserved R2TP complex (Rvb1-Rvb2-Tah1-Pih1), which interacts with Hsp90 to mediate assembly large protein complexes such as box C/D snoRNPs and RNA polymerase II [
]. PTH1 is also involved in pre-rRNA processing and required for the NOP58-snoRNA interaction [].
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 [,
,
].This family consists of several bacterial ABC transporter proteins which are homologous to the EcsB protein of Bacillus subtilis. EcsB is thought to encode a hydrophobic protein with six membrane-spanning helices in a pattern found in other hydrophobic components of ABC transporters [
].
Members of this family are a variant form of exosortase, XrtO, with a dedicated target typically encoded by the adjacent gene. Members have a unique C-terminal extension very different from EpsI (
), the extension that many exosortases have. The targets of XrtO all are members of the PEP-CTERM integral membrane protein family (
), which describes a PEP-CTERM protein about 950 residues long, found in more than 15 genera so far. These PEP-CTERM proteins are unusually hydrophobic in stretches, suggesting an integral membrane location, which is unusual. About one third of the members of IPR014270 are in genomes with this protein, exosortase O, always encoded by an adjacent gene.
This family represents the U3 small nucleolar ribonucleoprotein protein IMP4 and Ribosome production factor 1 RPF1 that belong to the IMP4 superfamily. This superfamily contains a Brix (biogenesis of ribosomes in Xenopus) domain, a region of 150-180 residues length, and it is characterised by the sigma70-like motif, a sequence motif first identified in the sigma70 family of prokaryotic transcription factors, which is sufficient to confer RNA binding activity [
,
,
]. IMP4 is a component of the 60-80S U3 small nucleolar ribonucleoprotein (U3 snoRNP) and it is required for the early cleavages during pre-18S ribosomal RNA processing [,
]. RPF1 is a essential protein involved in ribosome biogenesis [].
This probable domain is found in bacterial transcriptional regulators such as DeoR, SorC and CggR. One of these proteins,
, has an N-terminal helix-turn-helix
that binds to DNA. This domain is probably the ligand regulator binding region. SorC is regulated by sorbose and other members of this family are likely to be regulated by other sugar substrates. CggR regulates the gapA operon in B. subtilis [
].It is worth noting that the DeoR in this entry is represented by the protein, UniProt P39140, from Bacillus subtilis. Not the DeoR, UniProt P0ACK5, from E. coli. Despite sharing the same name, these two proteins do not share protein sequence similarity [
].
Neuromuscular junction formation relies upon the clustering of acetylcholine receptors and other proteins in the muscle membrane. Rapsyn (receptor-associated protein of the synapse) is a peripheral membrane protein that is selectively concentrated at the neuromuscular junction (NMJ) and is essential for the formation of synaptic acetylcholine receptor aggregates. It is required for anchoring and stabilising the nicotinic acetylcholine receptor (AChR) in the postsynaptic membrane of the NMJ [
]. Acetylcholine receptors fail to aggregate beneath nerve terminals in mice where rapsyn has been knocked out. The N-terminal six amino acids of rapsyn are its myristoylation site, and myristoylation is necessary for the targeting of the protein to the membrane [].
Proteins containing this domain are putative peptidases closely related to the M35 family (
). In this family the metal binding HEXXH motif is replaced with HRXXH. The exact function of these fungal proteins is unknown. Proteins containing this domain include members of the Zps1 (Zinc- and pH-regulated Surface protein) family [
]. Some of them are fungal allergens; including Asp f2, a major allergen from Aspergillus fumigatus, which reacts with serum from patients with ABPA (allergic bronchopulmonary aspergillosis) [], and pH-regulated antigen 1 (PRA1) from Candida albicans, which has a role in fungal morphogenesis and perhaps in the host-parasite interaction during candidal infection [].
This entry includes proteins with a G-patch domain and a RNA recognition motif domain, including mammalian splicing factor 45 (SPF45; also known as RNA-binding motif protein 17 or RBM17) and plant DNA-damage-repair/toleration protein DRT111 (also known as RSN2). SPF45 is an mRNA spliceosomal protein that is required for alternative splicing and the utilization of cryptic splice sites. The beta-110 mutation in the haemoglobin beta causes activation of a cryptic 3' splice site that is the cause of human beta-thalassemia (sickle-cell anemia) [
]. DRT111 is also required for pre-mRNA splicing, particularly the mRNA for receptor-like kinase SNC4, which activates the defence response to microbial pathogens in plants [].
E3 ubiquitin-protein ligase TRIM58, RING finger, HC subclass
Type:
Domain
Description:
TRIM58, also known as protein BIA2, is an erythroid E3 ubiquitin-protein ligase induced during late erythropoiesis. It binds and ubiquitinates the intermediate chain of the microtubule motor dynein (DYNC1LI1/DYNC1LI2), stimulating the degradation of the dynein holoprotein complex. It may participate in the erythroblast enucleation process through regulation of nuclear polarization. TRIM58 belongs to the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain [].
This domain can be found in coiled-coil domain-containing protein 66 (CCDC). It is approximately 160 amino acids in length. CCDC66 protein is detected mainly in the inner segments of photoreceptors in many vertebrates including mice and humans. It has been found in dogs, that a mutation in the CCDC66 gene causes generalized progressive retinal atrophy (gPRA). This shows that the protein encoded for by this gene is vital for healthy vision and guards against photoreceptor cell degeneration. The structure of CCDC66 proteins includes a heptad repeat pattern which contains at least one coiled-coil domain. There are at least two or more α-helices which form a cable-like structure [].
RnfH is a member of the ubiquitin superfamily. Members of the RnfH family strongly co-occur in two distinct gene neighbourhood contexts. In one it is associated with a START domain protein, a membrane protein SmpA and the transfer mRNA binding protein SmpB. This association suggests a possible role in the SmpB-tmRNA-based tagging and degradation system of bacteria, which is interesting given that other members of the ubiquitin system are analogously involved in protein-tagging and degradation across eukaryotes and various prokaryotes. The second context in which the RnfH genes are present is in a membrane associated complex involved in transporting electrons for various reductive reactions such as nitrogen fixation [].
This entry relates to TssR family members. TssR proteins have no predicted TM regions.The type VI secretion system (T6SS) is a supra-molecular bacterial complex that resembles phage tails. It is a toxin delivery systems which fires toxins into target cells upon contraction of its TssBC sheath [
]. Thirteen essential core proteins are conserved in all T6SSs: the membrane associated complex TssJ-TssL-TssM, the baseplate proteins TssE, TssF, TssG, and TssK, the bacteriophage-related puncturing complex composed of the tube (Hcp), the tip/puncturing device VgrG, and the contractile sheath structure (TssB and TssC). Finally, the starfish-shaped dodecameric protein, TssA, limits contractile sheath polymerization at its distal part when TagA captures TssA [].
This entry includes the periplasmic binding domain of aliphatic amidase expression-regulating protein (AmiC) that belongs to the type I periplasmic binding fold protein family. AmiC controls expression of the amidase operon by the ligand-triggered conformational switch. In the absence of ligand or presence of butyramide (repressor), AmiC (the ligand sensor and negative regulator) adopts an open conformation and inhibits the transcription antitermination function of AmiR by direct protein-protein interaction. In the presence of inducing ligands such as acetamide, AmiC adopts a closed conformation which disrupts a silencing AmiC-AmiR complex and the expression of amidase and other genes of the operon are induced [
,
].
This entry represents the N-terminal domain of Lissencephaly-1 (LIS1). LIS1 is required for nuclear migration in fungi, cell cycle progression in mammals, and the formation of a folded cerebral cortex in humans. They appear to regulate the mechanical behaviour of cytoplasmic dynein, the primary minus-end-directed microtubule motor [
]. Proteins containing this domain include:Platelet-activating factor acetylhydrolase IB subunit alpha, also known as Lissencephaly-1 protein [
].Nuclear distribution protein PAC1 from budding yeasts [
]. Fungal nuclear distribution protein nudF [
,
].Mutations in the LIS1 gene cause Lissencephaly-1, a classical lissencephaly characterised by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six-layered cortex [
].
Methylated-DNA-[protein]-cysteine S-methyltransferase, active site
Type:
Active_site
Description:
Synonym(s): 6-O-methylguanine-DNA methyltransferase, O-6-methylguanine-DNA-alkyltransferase, Methylated-DNA-[protein]-cysteine S-methyltransferase.This entry represents the active site of 6-O-methylguanine-DNA methyltransferases.The repair of DNA containing O6-alkylated guanine is carried out by DNA-[protein]-cysteine S-methyltransferase (). The major mutagenic and carcinogenic effect of methylating agents in DNA is the formation of O6-alkylguanine. The alkyl group at the O-6 position is transferred to a cysteine residue in the enzyme [
]. This is a suicide reaction since the enzyme is irreversibly inactivatedand the methylated protein accumulates as a dead-end product. Most, but not
all of the methyltransferases are also able to repair O-4-methylthymine. DNA-[protein]-cysteine S-methyltransferases are widely distributed and are found in various prokaryotic and eukaryotic sources [
].
This entry represents the SOCS (suppressors of cytokine signaling) box of SSB2 (SPRY domain-containing SOCS box proteins). SSB proteins contain a central SPRY domain and a C-terminal SOCS. SSB2 has been shown to interact with c-Met, the hepatocyte growth factor receptor [
,
]. It also regulates inducible nitric oxide synthase (iNOS) by targeting it for proteasomal degradation []. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions [
,
].
A number of genes are expressed exclusively in the retina, where they appear to control the specialised functions of various different cell types [
]. One of these retinal genes (termed FAM138A/B/C/F) is found within a region of subtelomeric DNA and exhibits polymorphic distribution among multiple chromosomes []. This gene encodes a putative 85-amino acid polypeptide (also known as retina-specific protein F379) that shares a high level of similarity with the retinal protein FAM138D; both also include a well-conserved N-terminal domain that is shared by a wide range of proteins, including podocalyxin-like protein 1, proto-oncogene c-Rel, suppressor of G2 allele of SKP1 homologue, and ubiquitin carboxyl-terminal hydrolase 19.
Electron transfer flavoprotein, beta-subunit, conserved site
Type:
Conserved_site
Description:
The electron transfer flavoprotein (ETF) [
,
]
serves as a specific electronacceptor for various mitochondrial dehydrogenases. ETF transfers electrons to
the main respiratory chain via ETF-ubiquinone oxidoreductase. ETF is anheterodimer that consist of an alpha and a beta subunit and which bind one
molecule of FAD per dimer. A similar system also exists in some bacteria.The beta subunit of ETF is a protein of about 28 Kd which is structurally
related to the bacterial nitrogen fixation protein fixA which could play arole in a redox process and feed electrons to ferredoxin.
The beta subunit protein is distantly related to and forms aheterodimer with the alpha subunit
.
ERdj5, also known as Dnajc10 (DnaJ homologue subfamily C member 10), JPDI or macrothioredoxin, is a protein containing an N-terminal DnaJ domain and four redox active TRX domains [
]. This entry comprises the first TRX domain of ERdj5 located after the DnaJ domain at the N-terminal half of the protein. ERdj5 is a ubiquitous protein localized in the endoplasmic reticulum (ER) and is abundant in secretory cells. It's transcription is induced during ER stress []. It interacts with BiP through its DnaJ domain in an ATP-dependent manner. BiP, an ER-resident member of the Hsp70 chaperone family, functions in ER-associated degradation and protein translocation [].
This entry represents a Rad53 binding domain (tudor domain) from yeast Rad9. In Saccharomyces cerevisiae (Baker s yeast), Rad9 is a key adaptor protein in DNA damage checkpoint pathways. DNA damage induces Rad9 phosphorylation and promotes the interaction between Rad9 and phosphorylated Rad53 [
]. This interaction is achieved through the Rad53 binding domain from Rad9 and the FHA domains from Rad53 () [
]. Confusingly, there is another Rad9 protein found in fission yeast and other eukaryotes (which is known as Ddc1 in budding yeast) that is also involved in DNA repair. However, these proteins are not related to the Rad9 proteins covered by this entry.
This is the N-terminal of the DNA repair protein Rad54 [
]. Rad54 functions in the recombinational DNA repair (RAD52) pathway. It dissociates RAD51 from nucleoprotein filaments formed on dsDNA and could be involved in the turnover of RAD51 protein-dsDNA filaments. Deficient mice also show significantly shorter telomeres than wild-type controls, indicating that the protein activity plays an essential role in telomere length maintenance in mammals. Non-homologous end joining (NHEJ) and homologous recombination (HR) represent the two major pathways of DNA double-strand break (DSB) repair in eukaryotic cells. LIG4 and RAD54L cooperate to support cellular proliferation, repair spontaneous DSBs, and prevent chromosome and single chromatid aberrations [,
].
This entry represents a region of bacterial and viral proteins that are typically between 126 and 146 amino acids in length. The signature is found at the C terminus in association with
and
. There are two completely conserved G residues that may be functionally important. Many of the proteins in this entry are annotated as fibronectin type III however there is little accompanying literature to confirm this. It is also found in tip attachment protein J (also known as host specificity protein J) from Enterobacteria phage lambda (Bacteriophage lambda), which attaches the virion to the host receptor LamB, inducing viral DNA ejection [
].
Phosphatidylethanolamine-binding proteins (PEBPs) are present in all three major phylogenetic divisions (eukaryotes, bacteria, archaea). The members in this subgroup are present in eukaryotes. Members here include those in plants such as Arabidopsis thaliana FLOWERING LOCUS (FT) and TERMINAL FLOWER1 (FT1), which function as a promoter and a repressor of the floral transitions respectively [
,
,
], as well as the mammalian Raf kinase inhibitory protein (RKIP), also known as phosphatidylethanolamine-binding protein 1 (PEBP-1), which inhibits MAP kinase (Raf-MEK-ERK), G protein-coupled receptor (GPCR) kinase and NFkappaB signaling cascades [,
]. Although their overall structures are similar, the members of the PEBP family have very different substrates and oligomerization states (monomer/dimer/tetramer).
Poly-beta-1,6 N-acetyl-D-glucosamine export porin PgaA
Type:
Family
Description:
Members of this protein family are the poly-beta-1,6 N-acetyl-D-glucosamine (PGA) export porin PgaA of Gram-negative bacteria. There is no counterpart in the poly-beta-1,6 N-acetyl-D-glucosamine biosynthesis systems of Gram-positive bacteria such as Staphylococcus epidermidis. The PGA polysaccharide adhesin is a critical determinant of biofilm formation. This enzyme exports PGA across the outer membrane. The PGA transported seems to be partially N-deacetylated since N-deacetylation of PGA by PgaB is needed for PGA export through the PgaA porin [
,
].This outer membrane protein contains a predicted C-terminal β-barrel porin domain and a N-terminal periplasmic superhelical domain containing tetratricopeptide repeats, which may mediate protein-protein interactions, perhaps with PgaB [
].
The KfrA family of proteins are encoded on plasmids, generally in or near gene clusters involved in stable inheritance functions. These proteins are thought to form an all-helical structure, consisting of an N-terminal helix-turn-helix DNA binding domain and an extended coiled-coil tail. The best-characterised KfrA protein, encoded on the broad host-range Plasmid RK2, is a site-specific DNA-binding protein whose operator overlaps its own promoter. The DNA-binding domain is essential for function, while the coiled-coil domain is probably responsible for formation of multimers, and may provide an example of a bridge to host structures required for plasmid partitioning [
].This entry represents the N-terminal DNA-binding domain.
This family includes a MazG-like NTP-PPase from Deinococcus radiodurans (DR2231), a putative NTP-PPase YP_001813558.1 from Exiguobacterium sibiricum and their bacterial homologues. DR2231 shows significant structural resemblance to MazG proteins, but is functionally related to the dimeric dUTPases [
,
]. It can hydrolyze dUTP into dUMP. DR2231-like proteins contain a well conserved divalent ion binding motif, EXXEX(12-28)EXXD, which is the identity signature for the all-α-helical NTP-PPase superfamily. Unlike normal dimeric dUTPase-like proteins with a central four-helix bundle forming the active site, YP_001813558.1 displays a very unusual interlaced segment-swapped dimer. It potentially prefers to hydrolyze dCTPs or its derivatives. YP_001813558.1-like proteins contain a variant divalent ion binding motif, EXXEX(12-28)AXXD [].
This entry includes IRE1/2 and related proteins. Human IRE1 is a transmembrane protein kinase essential for the endoplasmic reticulum (ER) unfolded protein response (UPR) [
,
,
,
,
,
,
]. IRE1 is activated by autophosphorylation through its cytoplasmic kinase domain, and this leads to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator [].Human IRE2 induces translational repression through 28S ribosomal RNA cleavage in response to ER stress [
]. However, mouse IRE2 does not have this function, instead, it plays a role in expression of the DDIT3 transcription factor, required for the unfolded-protein response, growth arrest and apoptosis [].
Neuromodulin (also known as GAP-43, pp46, B-50, F1, and P-57) [
] is an axonalmembrane protein associated with nerve growth. It is a major component of the
motile growth cones that form the tips of elongating axons. Neuromodulin is anhydrophilic protein of 210 to 240 amino acid residues, which binds calmodulin
and inhibits phosphatidylinositol phosphate kinase (PIP kinase). It isphosphorylated by protein kinase C, and regulates the binding of GTP to G(0)
[]. Neuromodulin contains an IQ motif.This entry represents a conserved region containing a serine residue which can be phosphorylated by protein kinase C [
] and which is adjacent to the calmodulin-binding domain.
NlpE is a bacterial outer membrane lipoprotein that is necessary for signalling by the Cpx pathway [
]. This pathway responds to cell envelope disturbances and increases the expression of periplasmic protein folding and degradation factors. While the molecular function of the NlpE protein is unknown, it may be involved in detecting bacterial adhesion to abiotic surfaces. In Escherichia coli and Salmonella typhi, NlpE is also known to confer copper tolerance in copper-sensitive strains of Escherichia coli, and may be involved in copper efflux and delivery of copper to copper-dependent enzymes []. This domain is found at the C terminus of the NlpE protein [].
This family consists of several avian apovitellenin I sequences. As part of the avian reproductive effort, large quantities of triglyceride-rich very-low-density lipoprotein (VLDL) particles are transported by receptor-mediated endocytosis into the female germ cells. Although the oocytes are surrounded by a layer of granulosa cells harbouring high levels of active lipoprotein lipase, non-lipolysed VLDL is transported into the yolk. This is because VLDL particles from laying chickens (Gallus gallus) are protected from lipolysis by apolipoprotein (apo)-VLDL-II, a potent dimeric lipoprotein lipase inhibitor [
]. Apo-VLDL-II is produced in the liver and secreted into the blood stream when induced by estrogen production in female birds.
This entry contains alpha and epsilon sarcoglycans.The sarcoglycan family proteins are single pass transmembrane proteins that are part of the dystrophin-associated glycoprotein complex (DGC), a multiprotein complex that links the actin cytoskeleton to the extracellular matrix in cardiac and skeletal muscle [
]. The DGC can be classified biochemically into three subcomplexes: the cytoplasmic subcomplex (contains dystrophin, the dystrobrevins and the syntrophins), the dystroglycan subcomplex and the sarcoglycan subcomplex. The function of the sarcoglycan subcomplex is not clear. However, mutations in alpha-, beta-, gamma- and delta-sarcoglycan cause different forms of autosomal recessive limb girdle muscular dystrophies (LGMD) demonstrating its importance for normal muscle function [].
Pre-mRNA-splicing regulator WTAP (Wilms' tumor 1-associating protein) is a regulatory subunit of the WMM N6-methyltransferase complex, a multiprotein complex that mediates N6-methyladenosine (m6A) formation, which acts as an epitranscriptomic marker [
,
]. It plays a role in the efficiency of mRNA splicing and processing, and mRNA stability []. In Drosophila, the homologous protein pfemale-lethal(2)D has been implicated in alternative splicing regulation of genes involved in sexual determination [] and is required for eye development []. FKBP12-interacting protein of 37kDa (AtFIP37, At3g54170), the homologue from Arabidopsis, may also have a role in splicing events []. AtFIP37 interacts with mRNA adenosine methylase (MTA, encoded by At4g10760) in vitro and in vivo [].
Plant viruses encode specific proteins known as movement proteins (MPs) to control their spread through plasmodesmata (PD) in walls between cells as well as from leaf to leaf via vascular-dependent transport. During this movement process, the virally encoded MPs interact with viral genomes for transport from the viral replication sites to the PDs in the walls of infected cells along the cytoskeleton and/or endoplasmic reticulum (ER) network. The virus is then thought to move through the PDs in the form of MP-associated ribonucleoprotein complexes or as virions [
]. The NS3 protein appears to function as an RNA silencing suppressor [].This superfamily includes ssRNA negative-strand crop plant tenuivirus NS3.
Telomerase protein component 1 (TP1/TLP1) or TEP1 is a protein component of two ribonucleoprotein (RNP) complexes: vaults and telomerase. Vaults are large RNP particles with a barrel-like structure (
). The telomerase RNP replenishes incomplete chromosome termini due to DNA replication. Mammalian TEP1 is an RNA-binding protein and is required for the association of vault RNA with the vault particle [,
]. The N-terminal part of TEP1 contains 4 copies of the TEP1 N-terminal repeat in tandem. The repeat is composed of 30 amino acids and occurs in combination with the TROVE () and NACHT (
) domains and with WD-40 repeats (see
) in the C-terminal part.
This conserved region is found at the N-terminal of the member proteins. It is located adjacent and N-terminal to the pinin/SKD/memA domain
. Members of this family have very varied localisations within the eukaryotic cell. Pinin is known to localise at the desmosomes and is implicated in anchoring intermediate filaments to the desmosomal plaque [
,
]. SDK2/3 is a dynamically localised nuclear protein thought to be involved in modulation of alternative pre-mRNA splicing []. MemA is a tumour marker preferentially expressed in human melanoma cell lines. A common feature of the members of this family is that they may all participate in regulating protein-protein interactions [].
This entry represents the trichohyalin-plectin-homology domain. This domain can be found in mitostatin (also known as trichoplein keratin filament-binding protein, TCHP) and related proteins [
,
]. Trichoplein keratin filament-binding protein (TCHP) may act as a 'capping' or 'branching' protein for keratin filaments in the cell periphery. It may regulate K8/K18 filament and desmosome organisation mainly at the apical or peripheral regions of simple epithelial cells [
]. In human, it acts as a tumor suppressor which has the ability to inhibit cell growth and be pro-apoptotic during cell stress. It inhibits cell growth in bladder and prostate cancer cells by a down-regulation of HSPB1 by inhibiting its phosphorylation [].
This entry represents the N-terminal domain of the phage P1 DarA protein, which is a internal capsid protein probably ejected along with the viral DNA and prevents degradation of viral DNA by the host type I restriction-modification antiviral defense system [
]. This alpha and beta fold domain contains a conserved aspartate, and an asparagine residue followed by a basic residue in a Nx+ motif [
]. This domain can also be found in the phage P1 hdf protein, a solo version of the domain. The hdf protein is also a component of the phage P1 head []. The domain might be involved in a counter-restriction activity [].
UL16 protein (also known as cytoplasmic envelopment protein 2) plays a role in capsid maturation including DNA packaging/cleavage [
]. In immunofluorescence studies [], UL16 was localised to the nucleus of infected cells in areas containing high concentrations of Human herpesvirus 2 (Herpes simplex virus 2) capsid proteins. These nuclear compartments have been described previously as viral assemblons [] and are distinct from compartments containing replicating DNA. Localization within assemblons argues for a role of UL16 encoded protein in capsid assembly or maturation [].UL94 is a human cytomegalovirus (HCMV) homologue that has been shown to be involved in facilitating secondary envelopment of virions [
].
The initiation of eukaryotic chromosomal DNA replication requires the formation of an active replicative helicase at the replication origins of chromosomes. Yeast Sld3 and its metazoan counterpart treslin are the hub proteins mediating protein associations critical for formation of the helicase. The Sld7 protein interacts with Sld3, and the complex formed is thought to regulate the function of Sld3. Although Sld7 is a non-essential DNA replication protein that is found in only a limited range of yeasts, its depletion slowed the growth of cells and caused a delay in the S phase. Structure analysis indicates that the N-terminal domain of Sld7 binds to the N-terminal region of Sld3 [].
The large subunit of [NiFe]-hydrogenase, as well as other nickel metalloenzymes, is synthesised as a precursor devoid of the metalloenzyme active site. This precursor then undergoes a complex post-translational maturation process that requires a number of accessory proteins. The hydrogenase expression/formation proteins (HupF/HypC) form a family of smallproteins that are hydrogenase precursor-specific chaperones required for this maturation process [
]. They are believed to keep the hydrogenase precursor in a conformation accessible for metal incorporation [,
].The signature pattern for this entry is 9 residues in length, located at the N terminus; all the proteins matched by this pattern start with a conserved Met-Cys dipeptide.
Mutations in the LGI/EPT gene can result in a special form of epilepsy, autosomal dominant lateral temporal epilepsy. The Epitempin protein (also known as Leucine-rich glioma-inactivated protein) was seen to contain a 130 amino acid repeat in its C-terminal section, although a sub-domain of 50 amino acids has now been further defined within this. The architecture and structural features of this repeat make it a likely member 7-bladed β-propeller fold [
].This protein has now been found in a number of proteins associated with neurological disorders suggesting that it may play a role in the development of epilepsy and other related conditions [
].
This entry represents the odorant response abnormal protein 4 (ODR-4)-like proteins from animals and plants. In C.elegans, ODR-4 and ODR-8 are required for localising a subset of odorant GPCRs to the cilia of olfactory neurons [
]. Olfactory receptors (ORs) are synthesised in endoplasmic reticulum of the olfactory neurons, trafficked to the cell surface membrane and transported to the tip of the olfactory cilium, where they bind with odorants. Various accessory proteins are required for proper targetting of different ORs to the cell membrane. ODR-4 was the first accessory protein to be described. ODR-4 plays a role in nociceptive neurons to mediate avoidance of high oxygen [].
This entry represents Lissencephaly-1 (LIS1) and homologues. LIS1 is required for nuclear migration in fungi, cell cycle progression in mammals, and the formation of a folded cerebral cortex in humans. They appear to regulate the mechanical behaviour of cytoplasmic dynein, the primary minus-end-directed microtubule motor [
]. Proteins in this entry include:Platelet-activating factor acetylhydrolase IB subunit alpha, also known as Lissencephaly-1 protein [
].Nuclear distribution protein PAC1 from budding yeasts [
]. Fungal nuclear distribution protein nudF [
,
].Mutations in the LIS1 gene cause Lissencephaly-1, a classical lissencephaly characterised by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six-layered cortex [
].
This superfamily represents the N-terminal dimerization domain of the Lsr2 protein, a bacterial nucleoid-associated protein involved in chromosome organization and global gene regulation. This protein binds AT-rich regions of the genome, including genomic islands acquired by horizontal gene transfer and regions encoding major virulence factors, such as the ESX secretion systems, the lipid virulence factors PDIM and PGL, and the PE/PPE families of antigenic proteins. Lsr2 has an N-terminal dimerization domain and a C-terminal DNA-binding domain. Besides enabling dimerization of Lsr2 monomers, structural studies on the N-terminal domain have shown that Lsr2 dimers show a self-associative propensity allowing chromosome compaction and gene regulation in response to external stress [
,
].
This entry represents the keratin-associated proteins, PMG type [
]. The major structural proteins of mammalian hair are the hair keratin intermediate filaments (KIFs) and the keratin-associated proteins (KRTAPs). In the hair cortex, hair keratins are embedded in an inter-filamentous matrix consisting of KRTAPs which are essential for the formation of a rigid and resistant hair shaft as a result of disulphide bonds between cysteine residues. There are essentially three groups of KRTAPs, viz: the high-sulphur (HS) and ultra-high-sulphur (UHS) KRTAPs (cysteine content: 16-30 and >30 mol%, respectively) and the high-glycine/tyrosine (HGT: 35-60 mol% glycine and tyrosine) KRTAPs.
Other groups of keratin-associated proteins include
and
.
This C-terminal domain of Regulatory factor X-associated protein (RFXAP) binds to RFXANK [
,
], the ankyrin-repeat regulatory factor X protein. RFXAP is part of the RFX complex, mutants of either RFXAP or RFXANK protein fail to bind to each other. RFX5 binds only to the RFXANK-RFXAP scaffold and not to either protein alone, and neither the scaffold nor RFX5 alone can bind DNA. The binding of the RFXANK-RFXAP scaffold to RFX5 leads to a conformational change in the latter that exposes the DNA-binding domain of RFX5. The DNA-binding domain of RFX5 anchors the RFX complex to MHC class II X and S promoter boxes [].
This entry represents heterogeneous nuclear ribonucleoproteins C and C-like.
The physiologically active form of human heterogeneous nuclear ribonucleoprotein C (hnRNPC) is a tetramer of isoforms hnRNPC1 and C2. It binds pre-mRNA and nucleates the assembly of 40S hnRNP particles. Single hnRNPC tetramers bind 230-240 nucleotides. It may play a role in the early steps of spliceosome assembly and pre-mRNA splicing. It interacts with poly-U tracts in the 3'-UTR or 5'-UTR of mRNA and modulates the stability and the level of translation of bound mRNA molecules [,
,
,
].Among the hnRNP C-like proteins is Raly, a protein described in mouse and humans [
].
Helicases have been classified in 5 superfamilies (SF1-SF5) [
]. All of the proteins bind ATP and, consequently, all of them carry the classical Walker A (phosphate-binding loop or P-loop), and Walker B (Mg2+-binding aspartic acid) motifs []. For the two largest groups, commonly referred to as SF1 and SF2, a total of seven characteristic motifs have been identified [] which are distributed over two structural domains, an N-terminal ATP-binding domain and a C-terminal domain.This entry represents the C-terminal domain.UvrD-like DNA helicases belong to SF1, but they differ from classical SF1/SF2 by a large insertion in each domain. UvrD-like DNA helicases unwind DNA with a 3'-5' polarity [
]. Crystal structures of several uvrD-like DNA helicases have been solved [
,
,
]. They are monomeric enzymes consisting of two domains with a common α-β RecA-like core. The ATP-binding site is situated in a cleft between the N terminus of the ATP-binding domain and the beginning of the C-terminal domain. The enzyme crystallizes in two different conformations (open and closed). The conformational difference between the two forms comprises a large rotation of the end of the C-terminal domain by approximately 130 degrees. This "domain swiveling"was proposed to be an important aspect of the mechanism of the enzyme [
].Some proteins that belong to the uvrD-like DNA helicase family are listed below:
Bacterial UvrD helicase. It is involved in the post-incision events of nucleotide excision repair and methyl-directed mismatch repair. It unwinds DNA duplexes with 3'-5' polarity with respect to the bound strand and initiates unwinding most effectively when a single-stranded region is present.Gram-positive bacterial pcrA helicase, an essential enzyme involved in DNA repair and rolling circle replication. The Staphylococcus aureus pcrA helicase has both 5'-3' and 3'-5' helicase activities. Bacterial rep proteins, a single-stranded DNA-dependent ATPase involved in DNA replication which can initiate unwinding at a nick in the DNA. It binds to the single-stranded DNA and acts in a progressive fashion along the DNA in the 3' to 5' direction.Bacterial helicase IV (helD gene product). It catalyzes the unwinding of duplex DNA in the 3'-5' direction.Bacterial recB protein. RecBCD is a multi-functional enzyme complex that processes DNA ends resulting from a double-strand break. RecB is a helicase with a 3'-5' directionality.Fungal srs2 proteins, an ATP-dependent DNA helicase involved in DNA repair. The polarity of the helicase activity was determined to be 3'-5'.
Flavoenzymes have the ability to catalyse a wide range of biochemical reactions. They are involved in the dehydrogenation of a variety of metabolites, in electron transfer from and to redox centres, in light emission, in the activation of oxygen for oxidation and hydroxylation reactions [
]. About 1% of all eukaryotic and prokaryotic proteins are predicted to encode a flavin adenine dinucleotide (FAD)-binding domain [].According to structural similarities and conserved sequence motifs,FAD-binding domains have been grouped in three main families: (i) theferredoxin reductase (FR)-type FAD-binding domain,(ii) the FAD-binding domains that adopt a Rossmann fold and (iii) the p-cresol methylhydroxylase (PCMH)-type FAD-binding domain [
].The FAD cofactor consists of adenosine monophosphate (AMP) linked to flavin mononucleotide (FMN) by a pyrophosphate bond. The AMP moiety is composed of the adenine ring bonded to a ribose that is linked to a phosphate group. The FMN moiety is composed of the isoalloxazine-flavin ring linked to a ribitol, which is connected to a phosphate group. The flavin functions mainly in a redox capacity, being able to take up two electrons from one substrate and release them two at a time to a substrate or coenzyme, or one at a time to an electron acceptor. The catalytic function of the FAD is concentrated in the isoalloxazine ring, whereas the ribityl phosphate and the AMP moiety mainly stabilise cofactor binding to protein residues [
].The PCMH-type FAD-binding domain consists of two α-β subdomains: one is composed of three parallel β-strands (B1-B3) surrounded by α-helices, and is packed against the second subdomain containing five antiparallel β-strands (B4-B8) surrounded by α-helices [
]. The two subdomains accommodate the FAD cofactor between them []. In the PCMH proteins the coenzyme FAD is also covalently attached to a tyrosine located outside the FAD-binding domain in the C-terminal catalytic domain [].This domain is found in:FAD-linked oxidases (N-terminal domain), such as vanillyl-alochol oxidase (
) [
], flavoprotein subunit of p-cresol methylhydroxylase () [
], D-lactate dehydrogenases (,
-cytochrome) [
], cholesterol oxidases () [
], and cytokinin dehydrogenase 1 () [
].Uridine diphospho-N-acetylenolpyruvylglucosamine reductase (MurB) (N-terminal domain) [
].CO dehydrogenase flavoprotein (N-terminal domain; [
]) family, which includes xanthine oxidase (domain 3) () [
], subunit A of xanthine dehydrogenase (domain 3) () [
], medium subunit of quinoline 2-oxidoreductase (QorM) () [
], and the beta-subunit of 4-hydroxybenzoyl-CoA reductase (HrcB) (N-terminal domain) () [
].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups [
]. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence [
]. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [,
,
,
,
]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [
,
,
].Several 7TM receptors have been cloned but their endogenous ligands are unknown; these have been termed orphan receptors. A novel GPCR (GPR4) from the critical myotonic dystrophy (DM) region on chromosome 19q13.3 has been sequenced [
,
]. The gene is intronless and contain an open reading frame encoding a protein of 362amino acids. Two isoforms of GPR4 are expressed in humans, differing in their 3'
untranslated region as a result of the use of alternate polyadenylation signals. GPR4 iswidely expressed, with higher levels in kidney, heart, and especially lung [
]. Sequenceanalysis suggests that GPR4 is a peptide receptor; it shares strongest similarity with
purinergic receptors and receptors for angiotensin II, platelet activating factor, thrombinand bradykinin [
,
].
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups [
]. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [,
,
,
,
]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [
,
,
].The term opioid refers to a class of substance that produces its effects
via the major classes of opioid receptor, termed mu, delta and kappa.The receptors are found in the CNS and certain smooth muscles: mu-opioid
receptors are believed to mediate analgesia, hypothermia, respiratorydepression, miosis, bradycardia, nausea, euphoria and physical dependence,
beta-endorphin being the most potent endogenous ligand; delta-receptorsmediate analgesia; and kappa-opioid receptors are believed to mediate
analgesia, sedation, miosis and diuresis, dynorphin being the most potentendogenous ligand.A human placental protein that binds opioid ligands with moderate affinity
has been provisionally classified as an opioid receptor. However, it isnot selective for kappa-ligands and is 93% similar to the human NK3
tachykinin receptor, although it doesn't bind tachykinins.
