SII-SWORD/CoKE huggingface dataset:
SRA-YDG (SRA_YDG)
Type: Domain

This domain has been termed SRA-YDG, for SET and Ring finger Associated, and because of the conserved YDG motif within the domain. Further characteristics of the domain are the conservation of up to 13 evenly spaced glycine residues and a VRV(I/V)RG motif. The domain is mainly found in plants and animals and in bacteria. In animals, this domain is associated with the Np95-like ring finger protein and the related gene product Np97, which contains PHD and RING FINGER domains and which is an important determinant in cell cycle progression. Np95 is a chromatin-associated ubiquitin ligase, binding to histones is direct and shows a remarkable preference for histone H3 and its N-terminal tail. The SRA-YDG domain contained in Np95 is indispensable both for the interaction with histones and for chromatin binding
in vivo
. In plants the SRA-YDG domain is associated with the SET domain, found in a family of histone methyl transferases, and in bacteria it is found in association with HNH, a non-specific nuclease motif .
Leucine zipper, homeobox-associated (Leu_zip_homeo)
Type: Domain

This region is a plant specific leucine zipper that is always found associated with a homeobox .
HAT (Half-A-TPR) repeat (HAT)
Type: Repeat

This entry represents the HAT repeat in Pre-mRNA-splicing factor SYF1, CLF1 and related proteins that bind RNA from eukaryotes and prokaryotes
.

The HAT (Half A TPR) repeat has a repetitive pattern characterised by three aromatic residues with a conserved spacing. They are structurally and sequentially similar to TPRs (tetratricopeptide repeats), though they lack the highly conserved alanine and glycine residues found in TPRs. The number of HAT repeats found in different proteins varies between 9 and 12. HAT-repeat-containing proteins appear to be components of macromolecular complexes that are required for RNA processing . The HAT motif has striking structural similarities to HEAT repeats (

), being of a similar length and consisting of two short helices connected by a loop domain, as in HEAT repeats. Some studies have suggested that the HAT repeats may be involved in protein-protein interactions . However, the HAT repeats of Arabidopsis HCF107 protein have been shown to bind RNA .
GAR domain (GAR_dom)
Type: Domain

The GAR (Gas2-related) domain is common in plakin family members and Gas2 family members. It has been shown to bind to microtubules probably through the flexible, positively charged central β-sheet formed by by five antiparallel β-strands .
GoLoco motif (GoLoco_motif)
Type: Conserved_site

In heterotrimeric G-protein signalling, cell surface receptors (GPCRs) are coupled to membrane-associated heterotrimers comprising a GTP-hydrolysing subunit G-alpha and a G-beta/G-gamma dimer. The inactive form contains the alpha subunit bound to GDP and complexes with the beta and gamma subunit. When the ligand is associated to the receptor, GDP is displaced from G-alpha and GTP is bound. GTP/G-alpha complex dissociates from the trimer and associates to an effector until the intrinsic GTPase activity of G-alpha returns the protein to GDP bound form. Reassociation of GDP bound G-alpha with G-beta/G-gamma dimer terminates the signal. Several mechanisms regulate the signal output at different stage of the G-protein cascade. Two classes of intracellular proteins act as inhibitors of G protein activation: GTPase activating proteins (GAPs), which enhance GTP hydrolysis (see

), and guanine dissociation inhibitors (GDIs), which inhibit GDP dissociation. The GoLoco or G-protein regulatory (GPR) motif found in various G-protein regulators acts as a GDI on G-alpha(i) .

The crystal structure of the GoLoco motif in complex with G-alpha(i) has been solved . It consists of three small α helices. The highly conserved Asp-Gln-Arg triad within the GoLoco motif participates directly in GDP binding by extending the arginine side chain into the nucleotide binding pocket, highly reminiscent of the catalytic arginine finger employed in GTPase-activating protein (see

). This addition of an arginine in the binding pocket affects the interaction of GDP with G-alpha and therefore is certainly important for the GoLoco GDI activity .

Some proteins known to contain a GoLoco motif are listed below:

Mammalian regulators of G-protein signalling 12 and 14 (RGS12 and RGS14), multifaceted signal transduction regulators.

Loco, the drosophila RGS12 homologue.

Mammalian Purkinje-cell protein-2 (Pcp2). It may function as a cell-type specific modulator for G protein-mediated cell signalling. It is uniquely expressed in cerebellar Purkinje cells and in retinal bipolar neurons.

Eukaryotic Rap1GAP. A GTPase activator for the nuclear ras-related regulatory protein RAP-1A.

Drosophila protein Rapsynoid (also known as Partner of Inscuteable, Pins) and its mammalian homologues AGS3 and LGN. They form a G-protein regulator family that also contains TPR repeats.
Phosphorylated immunoreceptor signalling ITAM (Phos_immunorcpt_sig_ITAM)
Type: Repeat

Phosphorylated immunoreceptor signalling motifs (ITAMs) exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases . Motif may be dually phosphorylated on tyrosine that links antigen receptors to downstream signalling machinery.
Lon protease, N-terminal domain (Lon_prtase_N)
Type: Domain

This entry represents the N-terminal substrate-binding domain of the Lon protease. This ATP-dependent enzyme, a serine peptidase belonging to the MEROPS peptidase family S16, is conserved in archaeal, bacterial and eukaryotic organisms and catalyses rapid turnover of short-lived regulatory proteins and many damaged or denatured proteins. In eukaryotes, the majority of the proteins are located in the mitochondrial matrix . In yeast, Pim1, is located in the mitochondrial matrix and required for mitochondrial function. It is constitutively expressed but is increased after thermal stress, suggesting that Pim1 may play a role in the heat shock response .

The structure of this domain has been determined and it represents a general protein and polypeptide interaction domain .
Olfactomedin-like domain (Olfac-like_dom)
Type: Domain

The olfactomedin-like or OLF domain is a module of ~260 residues present in metazoan secreted glycoproteins with a characteristic tissue-specific expression. The domain is named after bullfrog olfactomedin, an extracellular matrix protein of olfactory neuroepithelium, whereof it forms the C-terminal part. Other proteins of the olfactomedin family contain the OLF domain in the C-terminal part, while the N terminus is more variable. Proteins of the latrophilin subfamily have an OLF domain in the N-terminal extracellular part, C-terminal to a SUEL-type lectin domain, and their C-terminal part contains domains of the G-protein coupled receptors family 2. Some OLF domain proteins are involved in the formation of the extracellular matrix, e.g. bullfrog olfactomedin, sea urchin amassin and C. elegans unc-122. In addition, OLF domain proteins can function in developmental processes, e.g. noelin and tiarin .

Secondary structure predictions show that the OLF domain contains several β-strands . A disulfide bond between two conserved cysteines within the OLF domain of human myocilin is implicated in mutations associated with severe forms of primary open angle glaucoma .
Phosphatidylinositol 3-kinase, adaptor-binding domain (PI3K_ABD)
Type: Domain

Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that phosphorylate 4,5-bisphonate (PI(4,5) P2 or PIP2) at the 3-position of the inositol ring, and thus generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which, in turns, initiates a vast array of signaling events. PI3Ks can be grouped into three classes based on their domain organisation. Class I PI3Ks are heterodimers consisting of a p110 catalytic subunit and a regulatory subunit of either the p85 type (associated with the class IA p110 isoforms p110alpha, p110beta or p110delta) or the p101 type (associated with the class IB p110
isoform p110gamma). Common to all catalytic subunits are an N-terminal adaptor-binding domain (ABD) that binds to p85/p101, a Ras-binding domain (RBD), a putative membrane-binding domain (C2), a helical domain of unknown function, and a kinase catalytic domain .

PI3K_ABD is a small globular domain of about 100 residues in length with an α/β-sandwich topology .
Phox-associated domain (Phox_assoc)
Type: Domain

This domain is found associated with PX domains. The PX (phox) domain occurs in a variety of eukaryotic proteins associated with intracellular signalling pathways.
ParB-like, N-terminal domain (ParB_N)
Type: Domain

This entry represents the N-terminal domain of ParB proteins, predominantly found in bacteria. Proteins containing this domain include Escherichia coli plasmid protein ParB and mammalian Sulfiredoxin-1 (Srx). This domain is characterised by a highly conserved arginine motig, RRXR, known as the arginine patch, which is crucial for ParB DNA binding activity . Mutations in the corresponding ParB residues lead to loss of function and sub-cellular localisation defects in Bacillus subtilis . This pocket in ParB binds ribonucleotide cytidine triphosphate (CTP). CTP binding is necessary to stabilise the domain in a conformation that facilitates its interaction with ParA . CTP binding modulates the parS-binding affinity of ParB, whereas specific recognition of a parS motif stimulates CTP hydrolysis.

ParB plays a vital role in chromosome partitioning and nucleoid occlusion. These proteins are essential for ensuring proper chromosome segregation during cell division by binding to the DNA origin of replication and localising to both poles of the predivisional cell following DNA replication. ParB proteins share significant sequence and structural similarity with Sulfiredoxin (Srx), a sulfinic acid reductase identified in eukaryotes. Sequence comparison and phylogenetic analysis of the Srx and ParB protein families suggest that Srx evolved via truncation of ParB, resulting in the removal of the entire C-terminal half of the protein including the HTH domain . ParB comprises three highly conserved domains: an N-terminal nucleotide-binding domain (NBD)

, a central helix-turn-helix parS-binding domain

, non-structured linker region, and a C-terminal dimerisation domain

that tightly links the two subunits of the ParB dimer .
Raf-like Ras-binding (RBD_dom)
Type: Domain

Ras and heterotrimeric G proteins' alpha subunits are signal-transducing GTPases that cycle between inactive GDP-bound and active GTP-bound forms. The activities of these GTPases are regulated in part by GTPase-activating protein (GAPs) that stimulate hydrolysis of GTP, and guanine nucleotide exchange factors (GEFs) that stimulate GDP release. Ras and G alpha GTPases are prolific signalling molecules interacting with a spectrum of effector molecules and acting through more than one signalling pathway. The Ras-binding domain (RBD) is an independent domain of about 75 residues, which is sufficient for GTP-dependent binding of Ras and other G alpha GTPases. The RBD domain can be present singly or in tandem and it can be found associated with many other domains, such as PDZ, RGS, PID, PH, C1, DH, or protein kinase .

Structurally, the RBD domain of Raf-1 consists of a five-stranded mixed beta- sheet with an interrupted α-helix and two additional small α-helices. The structure of the RBD domain belongs to the ubiquitin α/β roll superfold and is similar to that of the RA domain despite the lack of significant sequence identity. The major interaction between Ras and Raf-1 RBD domain occurs between two antiparallel β-strands: β2 of Ras and β2 of RBD .

This entry represents the entire RBD domain.
cAMP-dependent protein kinase regulatory subunit, dimerization-anchoring domain (cAMP_dep_PK_reg_su_I/II_a/b)
Type: Domain

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .

In the absence of cAMP, Protein Kinase A (PKA) exists as an equimolar tetramer of regulatory (R) and catalytic (C) subunits . In addition to its role as an inhibitor of the C subunit, the R subunit anchors the holoenzyme to specific intracellular locations and prevents the C subunit from entering the nucleus. All R subunits have a conserved domain structure consisting of the N-terminal dimerization domain, inhibitory region, cAMP-binding domain A and cAMP-binding domain B. R subunits interact with C subunits primarily through the inhibitory site. The cAMP-binding domains show extensive sequence similarity and bind cAMP cooperatively.

Two types of regulatory (R) subunits exist -types I and II -which differ in molecular weight, sequence, autophosphorylation capability, cellular location and tissue distribution. Types I and II were further sub-divided into alpha and beta subtypes, based mainly on sequence similarity. This entry represents the dimerization-anchoring domain of types I-alpha, I-beta, II-alpha and II-beta regulatory subunits of PKA proteins.The dimerization-anchoring domain is located within the first 45 residues of each regulatory subunit, and forms a high affinity binding site for A-kinase-anchoring proteins (AKAPs) .
Pointed domain (Pointed_dom)
Type: Domain

The highly conserved PNT (or Pointed) domain is found within a subset of the Ets transcription factors, including mammalian Ets-1, Ets-2, Erg, Fli-1, GABPalpha, and Tel, as well as Drosophila Pnt-P2 and Yan. The PNT domain is structurally related to the larger group of SAM domains through a common tertiary arrangement of four α-helices. A role in protein-protein association has been established for the PNT domain .
Saposin A-type domain (SAP_A)
Type: Domain

The saposin A-type domain is a ~40 amino acid domain present in the saposin precursor, prosaposin, in the propeptides that are cleaved off in the activation reaction. The domain is named after the small lysosomal proteins, saposins, which serve as sphingolipid hydrolase activator proteins in vertebrates. The mammalian saposins are synthesized as a single precursor molecule (prosaposin) which contains four saposin B-type domains yielding the active saposins A, B, C and D after proteolytic cleavage, and two saposin A-type domains in the extremities that are removed in the activation reaction. The saposin A-type domain may play a role in targeting, as propeptides containing the saposin A-type domain of the C terminus of prosaposin and of the N-terminal part of pulmonary surfactant-associated protein B are involved in the transport to the lysosome and to secretory granules (lamellar bodies, which are lysosomal-like organelles), respectively .

Some proteins known to contain a saposin A-type domain:

Mammalian proactivator polypeptide, the saposin precursor (prosaposin) that is processed into saposins A, B, C and D.

Mammalian pulmonary surfactant-associated protein B (SP-B), a surface tension reducing surfactant secreted by type II epithelial cells.
Transcription factor Ste12 (Ste12)
Type: Family

This entry include a group of fungal transcription factors, including Ste12, Cph1, SteA and MST12. In S. cerevisiae, Ste12 mediates transcriptional induction of cell type-specific genes in response to pheromones . Aspergillus nidulans SteA, an homodomain-containing protein, is required for sexual reproduction . MST12 from Magnaporthe oryzae (rice blast fungus) may regulate genes involved in infectious hyphae growth and in the expression of the cell surface sensor MSB2 .
SWIB/MDM2 domain (SWIB_MDM2_domain)
Type: Domain

The SWI/SNF family of complexes, which are conserved from yeast to humans, are ATP-dependent chromatin-remodelling proteins that facilitate transcription activation . The mammalian complexes are made up of 9-12 proteins called BAFs (BRG1-associated factors). The BAF60 family have at least three members: BAF60a, which is ubiquitous, BAF60b and BAF60c, which are expressed in muscle and pancreatic tissues, respectively. BAF60b is present in alternative forms of the SWI/SNF complex, including complex B (SWIB), which lacks BAF60a. The SWIB domain is a conserved region found within the BAF60b proteins , and can be found fused to the C terminus of DNA topoisomerase in Chlamydia. This domain is also found in the Saccharomyces cerevisiae SNF12 protein, the eukaryotic initiation factor 2 (eIF2) and the Arabidopsis thaliana At1g31760 protein .

MDM2 is an oncoprotein that acts as a cellular inhibitor of the p53 tumour suppressor by binding to the transactivation domain of p53 and suppressing its ability to activate transcription . p53 acts in response to DNA damage, inducing cell cycle arrest and apoptosis. Inactivation of p53 is a common occurrence in neoplastic transformations. The core of MDM2 folds into an open bundle of four helices, which is capped by two small 3-stranded β-sheets. It consists of a duplication of two structural repeats. MDM2 has a deep hydrophobic cleft on which the p53 α-helix binds; p53 residues involved in transactivation are buried deep within the cleft of MDM2, thereby concealing the p53 transactivation domain.

The SWIB and MDM2 domains are homologous and share a common fold.
Chemotaxis methyl-accepting receptor Tar-related, ligand-binding (Tar_rcpt_lig-bd)
Type: Domain

Methyl-accepting chemotaxis proteins (MCPs) are a family of bacterial receptors that mediate chemotaxis to diverse signals, responding to changes in the concentration of attractants and repellents in the environment by altering swimming behaviour . Environmental diversity gives rise to diversity in bacterial signalling receptors, and consequently there are many genes encoding MCPs . For example, there are four well-characterised MCPs found in Escherichia coli: Tar (taxis towards aspartate and maltose, away from nickel and cobalt), Tsr (taxis towards serine, away from leucine, indole and weak acids), Trg (taxis towards galactose and ribose) and Tap (taxis towards dipeptides).

This entry represents the ligand-binding domain found in a number of methyl-accepting chemotaxis receptors, such as E.coli Tar (taxis to aspartate and repellents), which is a receptor for the attractant L-aspartate . It is a homodimeric receptor that contains an N-terminal periplasmic ligand binding domain, a transmembrane region, a HAMP domain and a C-terminal cytosolic signaling domain .
VPS9 domain (VPS9)
Type: Domain

Rab proteins form a family of signal-transducing GTPases that cycle between
active GTP-bound and inactive GDP-bound forms. The Rab5 GTPase is an essential
regulator of endocytosis and endosome biogenesis. Rab5 is activated by GDP-GTP
exchange factors (GEFs) that contain a VPS9 domain and generate the Rab5-GTP
complex .

The VPS9 domain catalyzes nucleotide exchange on Rab5 or the yeast homologue VPS21. The domain has a length of ~140 residues and forms the central part of the yeast VPS9 (vacuolar protein sorting-associated) protein, which acts as a GEF for VPS21. Some domains which can occur in combination with the VPS9 domain are CUE, A20-type zinc finger, Ras-associating (RA), SH2, RCC1, DH, PH, rasGAP, MORN and ankyrin repeat.

Structurally, the VPS9 domain adopts a layered fold of six α helices. Conserved residues from the fourth and sixth helices and the loops N-terminal to these helices form the surface that interacts with Rab5 and Rab21 .

Some proteins known to contain a VPS9 domain:

Fungal Vacuolar Protein Sorting-associated protein VPS9, a guanine nucleotide exchange factor for the Rab-like GTPase VPS21. VPS9 is needed for the transport of proteins from biosynthetic and endocytic pathways into the vacuole.

Mammalian Rab5 GDP/GTP exchange factor or Rabex-5 (Rababtin-5 associated exchange factor for Rab5), catalyzes nucleotide exchange on RAB5A. Rabex-5 promotes endocytic membrane fusion and is involved in membrane trafficking of recycling endosomes.

Mammalian Ras and Rab interactor 1 (RIN1), 2 (RIN2) and 3 (RIN3).

Mammalian alsin or Amyotrophic Lateral Sclerosis protein 2 (ALS2). Different juvenile-onset forms of neurodegenerative diseases (ALS2, JPLS, IAHSP) are caused by mutations in the ALS2 gene, which result in truncated alsin lacking the C-terminal part of the VPS9 domain.

Fruit fly protein sprint, which is a RIN homologue.

Caenorhabditis elegans RME-6 protein, which is conserved among metazoans.
WH2 domain (WH2_dom)
Type: Domain

The WH2 (WASP-Homology 2, or Wiskott-Aldrich homology 2) domain is an ~18 amino acids actin-binding motif. This domain was first recognised as an essential element for the regulation of the cytoskeleton by the mammalian Actin nucleation-promoting factor WAS (also known asWiskott-Aldrich syndrome protein, WASP). WH2 proteins occur in eukaryotes from yeast to mammals, in insect viruses, and in some bacteria. The WH2 domain is found as a modular part of larger proteins; it can be associated with the WH1 or EVH1 domain

and with the CRIB domain

, and the WH2 domain can occur as a tandem repeat. The WH2 domain binds actin monomers and can facilitate the assembly of actin monomers into newly forming actin filaments .

Some proteins known to contain a WH2 domain:

Mammalian Actin nucleation-promoting factor WAS (WASP), a possible regulator of lymphocyte and platelet function. Defects in WASP are the cause of Wiskott- Aldrich syndrome (WAS), an X-linked recessive disease characterised by immune dysregulation and microthrombocytopenia. WASP proteins bind the actin nucleating protein complex Arp2/3.

Mammalian N-WASP/WASL and WASF/SCAR/WAVE1-3, and yeast LAS17, which are also proteins from the WASP family that participate in the transduction of signals from the cell surface to the actin cytoskeleton.

WAS protein family homologue 1 (WASH1), acts as a nucleation-promoting factor at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerisation.

Baker's yeast Verprolin, a protein involved in cytoskeletal organisation and cellular growth.

Human WASP interacting protein (WASPIP/WIP), a WASP-, profilin- and actin-binding protein which induces actin polymerisation and redistribution.

Nuclear polyhedrosis virus (NPV) P61/78/83 capsid protein, which may be important for the persistence and survival of the virus.

Fruit fly Spir(e) protein, an actin nucleation factor involved in the development of oocytes and embryos. Spir is conserved among metazoans.

Mammalian metastasis suppressor 1 or Missing in Metastasis (MIM) protein, an actin-binding protein that may be related to cancer progression or tumor metastasis.
Domain of unknown function WSN (WSN)
Type: Domain

This domain has no known function and is found in Caenorhabditis elegans proteins normally at the N-terminal.