SII-SWORD/CoKE huggingface dataset:
Signal transduction response regulator with modified HD-GYP domain, putative (Sig_transdc_resp-reg_put)
Type: Family

This entry represents a group of signal transduction response regulators which contain a modified version of the HD-GYP domain as an output domain.

Response regulators of the microbial two-component signal transduction systems typically consist of an N-terminal CheY-like receiver (phosphoacceptor) domain and a C-terminal output (usually DNA-binding) domain. In response to an environmental stimulus, a phosphoryl group is transferred from the His residue of sensor histidine kinase to an Asp residue in the CheY-like receiver domain of the cognate response regulator . Phosphorylation of the receiver domain induces conformational changes that activate an associated output domain, which in turn triggers the response. Phosphorylation-induced conformational changes in response regulator molecule have been demonstrated in direct structural studies .

HD-GYP is a conserved domain found in response regulator modules of various signal transduction systems. The involvement of the HD-GYP domain in signal transduction was originally proposed on the basis of its association with CheY-like and other signal transduction domains and was later directly demonstrated experimentally by showing that RpfG is involved in regulation of the biosynthesis of extracellular endoglucanase and polysaccharide .

A modification of the HD-GYP domain, which is found in this group,

, and several smaller groups, lacks the conserved distal portion of the domain and has certain substitutions in the characteristic metal-binding residues of the HD superfamily phosphohydrolases, which likely render it catalytically inactive. Note that the prototypical HD domain (

) is not recognised in many members of this group.

The exact mode of action and targets of the HD-GYP output domain are not known . HD-GYP proteins are associated to the HD domain superfamily of metal-dependent phosphohydrolases; HD designates the principal conserved residues implicated in metal binding and catalysis . The HD-GYP version of the HD-type domain has many additional highly conserved residues, including a conserved GYP motif, hence its name .

It has been noted that the highly conserved sequence of the HD-GYP domain suggests high substrate specificity . On the basis of its association with the GGDEF diguanylate cyclase domain, it has been also predicted that the HD-GYP domain may be involved in the metabolism of cyclic diguanylate or in dephosphorylation of some phosphotransfer domain .
Uncharacterised conserved protein UCP036888, signal transduction HD-GYP-like, PA5346 type (UCP036888_HDGYP-like)
Type: Family

Members of this group contain a modified version of the HD-GYP domain and an uncharacterised N-terminal domain. There is currently no experimental data for members of this group.

HD-GYP is a conserved domain found in response regulator modules of various signal transduction systems. The involvement of the HD-GYP domain in signal transduction was originally proposed on the basis of its association with CheY-like and other signal transduction domains and was later directly demonstrated experimentally by showing that RpfG is involved in regulation of the biosynthesis of extracellular endoglucanase and polysaccharide .

A modification of the HD-GYP domain, which is found in this group,

, and several smaller groups, lacks the conserved distal portion of the domain and has certain substitutions in the characteristic metal-binding residues of the HD superfamily phosphohydrolases, which likely render it catalytically inactive. Note that the prototypical HD domain (

) is not recognised in many members of this group.

The exact mode of action and targets of the HD-GYP output domain are not known . HD-GYP proteins are associated to the HD domain superfamily of metal-dependent phosphohydrolases; HD designates the principal conserved residues implicated in metal binding and catalysis . The HD-GYP version of the HD-type domain has many additional highly conserved residues, including a conserved GYP motif, hence its name .

It has been noted that the highly conserved sequence of the HD-GYP domain suggests high substrate specificity . On the basis of its association with the GGDEF diguanylate cyclase domain, it has been also predicted that the HD-GYP domain may be involved in the metabolism of cyclic diguanylate or in dephosphorylation of some phosphotransfer domain .
Mannose-6-phosphate isomerase, Firmicutes type, short form (Man6P_isomerase_Firm_short)
Type: Family

Mannose-6-phosphate isomerase or phosphomannose isomerase (

) (PMI) is the enzyme that catalyses the interconversion of mannose-6-phosphate and fructose-6-phosphate. In eukaryotes PMI is involved in the synthesis of GDP-mannose, a constituent of N-and O-linked glycans and GPI anchors and in prokaryotes it participates in a variety of pathways, including capsular polysaccharide biosynthesis and D-mannose metabolism. PMI's belong to the cupin superfamily whose functions range from isomerase and epimerase activities involved in the modification of cell wall carbohydrates in bacteria and plants, to non-enzymatic storage proteins in plant seeds, and transcription factors linked to congenital baldness in mammals . Three classes of PMI have been defined .

This group represents a mannose-6-phosphate isomerase, Firmicutes type, short form.
Cellular repressor of E1A-stimulated genes (CREG) (CREG)
Type: Family

CREG (cellular repressor of E1A-stimulated genes) is a secreted glycoprotein that inhibits cell growth in different cell types. CREG binds M6P(mannose-6-phosphate)/IGF2R(insulin-like growth factor II receptor) and mediates cell growth and is involved in cell differentiation in the nervous system. Although the CREG protein is extraordinarily well conserved throughout evolution from plants to mammals, it lacks any recognisable protein motifs or domains . Another CREG family member, CREG2, has been identified and characterised . CREG2 is expressed specifically in brain tissue.
Alpha-amylase, MalS type (A_amylase_MalS)
Type: Family

Alpha-amylase is classified as family 13 (

) of the glycosyl hydrolases and is present in archaea, bacteria, fungi, plants and animals. Alpha-amylase is an essential enzyme in alpha-glucan metabolism, acting to catalyse the hydrolysis of alpha-1,4-glucosidic bonds of glycogen, starch and related polysaccharides. Although all alpha-amylases possess the same catalytic function, they can vary with respect to sequence. In general, they are composed of three domains: a TIM barrel containing the active site residues and chloride ion-binding site (domain A), a long loop region inserted between the third β-strand and the α-helix of domain A that contains calcium-binding site(s) (domain B), and a C-terminal β-sheet domain that appears to show some variability in sequence and length between amylases (domain C) . Amylases have at least one conserved calcium-binding site, as calcium is essential for the stability of the enzyme. The chloride-binding functions to activate the enzyme, which acts by a two-step mechanism involving a catalytic nucleophile base (usually an Asp) and a catalytic proton donor (usually a Glu) that are responsible for the formation of the beta-linked glycosyl-enzyme intermediate.

This group represents an alpha-amylase, MalS type. Periplasmic alpha-amylase from Escherichia coli, the malS gene product, hydrolyses linear maltodextrins. MalS is monomeric and has four cysteine residues, which are involved in intramolecular disulphide bonds .
RNase H, phosphoglycerate mutase domain-containing (RNaseH/PGlycerate_mutase)
Type: Family

These proteins contain an RNase H domain (

) followed by a phosphoglycerate mutase family domain (

). The protein from Corynebacterium glutamicum appears to be a functional RNase H (

). Protein Rv2228c is the only known endonuclease from
Mycobacterium tuberculosis
with RNase H activity, catalysing the hydrolysis of the phospho group from alpha-ribazole 5'-phosphate to form alpha-ribazole . The function of the phosphoglycerate mutase domain family is unknown.
Sorting nexin-5/6/32 (SNX5/SNX6/SNX32)
Type: Family

Sorting nexins (SNXs) are a diverse group of cellular trafficking proteins that are unified by the presence of a phospholipid-binding motif, the PX domain. The ability of these proteins to bind specific phospholipids, as well as their propensity to form protein-protein complexes, points to a role for these proteins in membrane trafficking and protein sorting . Members of this group also contain coiled-coil regions within their large C-terminal domains and a BAR domain, whose function has been defined as a dimerisation motif, as sensing and inducing membrane curvature, and/or likely to bind to small GTPases .

This entry includes SNX5, SNX6 and SNX32 (also known as SNX6B).

SNX5 contains a BAR domain that is C teminus to the PX domain. SNX5 plays a role in macropinocytosis and in the internalisation of EGFR after EGF stimulation .

SNX6 was found to interact with members of the transforming growth factor-beta family of receptor serine/threonine kinases. Strong heteromeric interactions were also seen among SNX1, -2, -4, and -6, suggesting the formation
in vivo
of oligomeric complexes. SNX6 is localized in the cytoplasm where it is thought to target proteins to the
trans
-Golgi network . In addition, SNX6 was found to be translocated from the cytoplasm to nucleus by Pim-1, an oncogene product of serine/threonine kinase. This translocation is not affected by Pim-1-dependent phosphorylation, but the functional significance is unknown .
Double C2 protein, alpha/beta/gamma (Doc2)
Type: Family

Neurotransmitter release from nerve termini in the brain is regulated by several families of Ca
2+
-binding proteins with tandem C2 domains (

) . The C2 domain confers the ability to binding phospholipids in a Ca
2+
-dependent fashion.

Doc2 (double C2-like domain-containing protein) has one Munc13-interacting domain (Munc13 is a peripheral membrane protein in the plasma membrane of nerve termini). The interaction between Doc2 and Munc13-1 is thought to underlie the molecular mechanism of phorbol ester enhancement of neurotransmitter release .

Doc2 consists of three isoforms, Doc2alpha, beta and gamma. Doc2alpha is specifically expressed in neuronal cells and has been implicated in Ca
2+
-dependent neurotransmitter release, whereas Doc2beta is ubiquitously expressed . In contrast to the other Doc2 isoforms, the C2 domains of Doc2gamma lacks the Ca
2+
-dependent phospholipid binding activity. The highest expression of Doc2gamma mRNA is found in the heart, but occurs ubiquitously, the same as Doc2beta. Doc2gamma may also function as an effector for Munc13-1 and may be involved in the regulation of vesicular trafficking .
Imidazole glycerol phosphate synthase HisHF (IGPS_HisHF)
Type: Family

Members of this group are eukaryotic bifunctional enzymes with glutamine amidotransferase (

) and cyclase activities (

) that catalyse the fifth and sixth steps of the histidine biosynthetic pathway. In eubacteria, these steps are catalysed by a complex formed by two subunits, namely the glutamine amidotransferase HisH (

) and the cyclase HisF which are encoded in the same operon .

The catalytic activity has been assessed for many members, mainly by complementation assays. The Saccharomyces cerevisiae (Baker's yeast) member is able to suppress His auxotrophy of corresponding Escherichia coli hisH and hisF mutants . In plants, hisHF cDNA from Emericella nidulans (Aspergillus nidulans) and Arabidopsis thaliana (Mouse-ear cress) complemented a S. cerevisiae
his7Delta
strain . In addition, A. nidulans cDNA complemented E. coli
hisH
and
hisF
mutant strains .
Protein arginine N-methyltransferase PRMT7 (MeTrfase_PRMT7)
Type: Family

This entry represents protein arginine N-methyltransferase PRMT7 .

PRMT7 can catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA. It mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. It also mediates the symmetric dimethylation of histone H4 'Arg-3' to form H4R3me2s. It plays a role in gene imprinting by being recruited by CTCFL at the H19 imprinted control region (ICR) and methylating histone H4 to form H4R3me2s, possibly leading to recruit DNA methyltransferases at these sites. It may also play a role in embryonic stem cell (ESC) pluripotency .
Target of Myb protein 1 (TOM1)
Type: Family

Tom1 (target of Myb 1) and its related proteins (Tom1L1 and Tom1L2) constitute a protein family and share an N-terminal VHS (Vps27p/Hrs/Stam) domain followed by a GAT (GGA and Tom1) domain.

VHS domains are found at the N termini of select proteins involved in intracellular membrane trafficking and are often localized to membranes. The three dimensional structure of human TOM1 VHS domain reveals eight helices arranged in a superhelix. The surface of the domain has two main features: (1) a basic patch on one side due to several conserved positively charged residues on helix 3 and (2) a negatively charged ridge on the opposite side, formed by residues on helix 2 . The basic patch is thought to mediate membrane binding.

It was demonstrated that the GAT domain of both Tom1 and Tom1L1 binds ubiquitin, suggesting that these proteins might participate in the sorting of ubiquitinated proteins into multivesicular bodies (MVB) . Moreover, Tom1L1 interacts with members of the MVB sorting machinery. Specifically, the VHS domain of Tom1L1 interacts with Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate), whereas a PTAP motif, located between the VHS and GAT domains of Tom1L1, is responsible for binding to TSG101 (tumour susceptibility gene 101). Myc epitope-tagged Tom1L1 is recruited to endosomes following Hrs expression. In addition, Tom1L1 possesses several tyrosine motifs at the C-terminal region that mediate interactions with members of the Src family kinases and other signalling proteins such as Grb2 and p85. Expression of a constitutively active form of Fyn kinase promotes the recruitment of Tom1L1 to enlarged endosomes. It is proposed that Tom1L1 could act as an intermediary between the signalling and degradative pathways .

Over expression of Tom1 suppresses activation of the transcription factors NF-kappaB and AP-1, induced by either IL-1beta or tumour necrosis factor (TNF)-alpha, and the VHS domain of Tom1 is indispensable for this suppressive activity. This suggests that Tom1 is a common negative regulator of signalling pathways induced by IL-1beta and TNF-alpha .
Replication factor A protein 2 (Rfa2/RPA32)
Type: Family

Rfa2 (also known as RPA32) is a component of the replication protein A (RPA) complex, which binds to and removes secondary structure from ssDNA. The RPA complex is involved in DNA replication, repair, and recombination .
CST complex subunit Stn1 (Stn1)
Type: Family

Stn1 is a component of the CST complex, a complex that binds to single-stranded DNA and is required to protect telomeres from DNA degradation. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. In addition to telomere protection, the CST complex has probably a more general role in DNA metabolism at non-telomeric sites .
Neuropilin (Neuropilin)
Type: Family

Neuropilins are essential multifunctional vertebrate cell surface receptors . They function as receptors for axon guidance factor semaphorin class 3 (Sema3), vascular endothelial growth factor (VEGF) and placenta growth factor-2 (PLGF-2).
Uncharacterised conserved protein, 2xCBS, MJ1404 type (UCP036983_2CBS_MJ1404)
Type: Family

This group represents an uncharacterised protein with 2 CBS domain pairs, MJ1404 type.
Synaptotagmin-17, C2B domain (Syt17_C2B)
Type: Domain

Synaptotagmin-17 (SYT17) belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains. Although synaptotagmins have been found to have a unique N-terminal domain that is involved in membrane anchoring (e.g., synaptotagmin) or specific ligand binding (e.g., rabphilin-3A and Doc2,

), SYT17 does not contain this domain. This protein is highly expressed in brain and kidney (B/K) . Despite the lack of a transmembrane domain, it is tightly bound to the membrane fraction after treatment with high concentration of salt or high pH. Deletion and mutation analyses indicate that the cysteine cluster at the N terminus is essential for membrane localisation of SYT17. When wild-type SYT17 is expressed in PC12 cells, SYT17 proteins are localised mainly to the perinuclear region (trans-Golgi network), whereas mutant SYT17 carrying Cys-to-Ala substitutions are cytosolic .

This entry represents the second and C-terminal C2 domain (C2B), responsible for the binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence. It also regulates also the recycling step of synaptic vesicles. This domain folds into an eight-standed β-sandwich with a Type I arrangement that shows a circular permutation involving their N- and C-terminal β-strands .
Glutathione synthase, C-terminal, eukaryotic (Glutathione_synthase_C_euk)
Type: Homologous_superfamily

This superfamily represents the C-terminal domain found in eukaryotic glutathione synthetase (

) (GSS), a homodimeric enzyme that catalyses the conversion of gamma-L-glutamyl-L-cysteine and glycine to phosphate and glutathione in the presence of ATP. This is the second step in glutathione biosynthesis, the first step being catalysed by gamma-glutamylcysteine synthetase . In humans, defects in GSS are inherited in an autosomal recessive way and are the cause of severe metabolic acidosis, 5-oxoprolinuria, and increased rate of haemolysis and defective function of the central nervous system.

This domain has a 2-layer α/β structure.
RmlC-like jelly roll fold (RmlC-like_jellyroll)
Type: Homologous_superfamily

RmlC (deoxythymidine diphosphates-4-dehydrorhamnose 3,5-epimerase;

) is a mainly beta class protein with a jelly roll-like topology. It is a dTDP-sugar isomerase enzyme involved in the synthesis of L-rhamnose, a saccharide required for the virulence of some pathogenic bacteria . This entry represents the domain with the jelly roll-like fold.
ANTH domain superfamily (ANTH_dom_sf)
Type: Homologous_superfamily

The AP180 N-terminal homology (ANTH) domain is a membrane binding domain found in endocytotic accessory proteins, such as AP180. The ANTH domain is involved in phosphatidylinositol 4,5-bisphosphate (also known as PIP2) binding and is also responsible for membrane localisation of AP180. The ANTH domain containing proteins appear to be universal elements in nucleation of clathrin coats .

The N-terminal phosphoinositide-binding domain of CALM and AP180 consist of nine α helices forming a solenoid structure. This is most similar to the ENTH domain of epsin, with the first seven helices of epsin superimposing well on those of CALM. However, in epsin the final alpha8 helix folds back across the others, whereas in CALM and AP180 the final three long helices continue the solenoidal pattern .
Glutamate mutase E subunit, C-terminal domain superfamily (Glu_mut_E_C_dom_sf)
Type: Homologous_superfamily

Glutamate mutase (methylaspartate mutase) catalyses the reversible interconversion of L-glutamate and L-threo-3-methylaspartate, the first step in the pathway of glutamate fermentation . Catalysis is initiated using the cobalamin cofactor. The E subunit is the catalytic subunit (MutE) . This superfamily represents the C-terminal domain.
Fibrinogen, alpha/beta/gamma chain, C-terminal globular, subdomain 1 (Fibrinogen_a/b/g_C_1)
Type: Homologous_superfamily

Fibrinogen plays key roles in both blood clotting and platelet aggregation. During blood clot formation, the conversion of soluble fibrinogen to insoluble fibrin is triggered by thrombin, resulting in the polymerisation of fibrin, which forms a soft clot; this is then converted to a hard clot by factor XIIIA, which cross-links fibrin molecules. Platelet aggregation involves the binding of the platelet protein receptor integrin α(IIb)-β(3) to the C-terminal D domain of fibrinogen . In addition to platelet aggregation, platelet-fibrinogen interaction mediates both adhesion and fibrin clot retraction.

This superfamily represents a subdomain of the C-terminal globular D domain found in fibrinogen alpha, beta and gamma chains, and related domains found in protein involved in protein or cell binding.
Translation elongation factor EF1B/small ribosomal subunit protein bS6 (Transl_elong_EF1B/ribsomal_bS6)
Type: Homologous_superfamily

An α+β sandwich domain with a Ferredoxin-like fold can be found in the beta chain of the translation elongation factor EF1B , and in the small ribosomal subunit protein bS6 (ribosomal protein S6) .

Elongation factor EF1B (also known as EF-Ts or EF-1beta/gamma/delta) is a nucleotide exchange factor that is required to regenerate EF1A from its inactive form (EF1A-GDP) to its active form (EF1A-GTP). EF1A is then ready to interact with a new aminoacyl-tRNA to begin the cycle again. EF1B is more complex in eukaryotes than in bacteria, and can consist of three subunits: EF1B-alpha (or EF-1beta), EF1B-gamma (or EF-1gamma) and EF1B-beta (or EF-1delta) .
Glycoside hydrolase-type carbohydrate-binding (GH-type_carb-bd)
Type: Homologous_superfamily

This superfamily represents a domain with a distorted supersandwich structure consisting of 18 strands in two sheets, which probably functions to bind carbohydrates in enzymes that act on sugars. Domains with this structure occur in several protein families, including galactose mutarotase (

); domain 5 of beta-galactosidase (

); the central domain of hyaluronate lyase-like enzymes, such as chondroitinase AC (

), chrondroitin ABC lyase I, and hyaluronate lyase (

) itself ; and the N-terminal domain of bacterial glucoamylase (

) and rhamnogalacturonate lyase (

).