SII-SWORD/CoKE huggingface dataset:
Tetraspanin, EC2 domain superfamily (Tetraspanin_EC2_sf)
Type: Homologous_superfamily

This superfamily represents the EC2 domain from tetraspanins, consisting of 5 helices in an irregular disulphide-linked array which plays a role in form homodimerization.

Tetraspanins are a distinct family of cell surface proteins, containing four conserved transmembrane domains: a small outer loop (EC1), a larger outer loop (EC2), a small inner loop (IL) and short cytoplasmic tails. They contain characteristic structural features, including 4-6 conserved extracellular cysteine residues, and polar residues within transmembrane domains.

A fundamental role of tetraspanins appears to be organising other proteins into a network of multimolecular membrane microdomains, sometimes called the 'tetraspanin web'. Within this web there are primary complexes in which tetraspanins show robust, specific, and direct lateral associations with other proteins. The strong tendency of tetraspanins to associate with each other probably contributes to the assembly of a network of secondary interactions in which non-tetraspanin proteins are associated with each other via palmitoylated tetraspanins acting as linker proteins. In addition, the association of lipids, such as gangliosides and cholesterol, probably contributes to the assembly of even larger tetraspanin complexes, which have some lipid raft-like properties (e.g. resistance to solubilization in non-ionic detergents). Within the tetraspanin web, tetraspanin proteins can associate not only with integrins and other transmembrane proteins, but also with signalling enzymes such as protein kinase C and phosphatidylinositol-4 kinase. Thus, the tetraspanin web provides a mechanistic framework by which membrane protein signalling can be expanded into a lateral dimension .
Iron hydrogenase, small subunit HydB-type (Fe_hydrogenase_HydB)
Type: Homologous_superfamily

Many microorganisms, such as methanogenic, acetogenic, nitrogen-fixing, photosynthetic, or sulphate-reducing bacteria, metabolise hydrogen. Hydrogen activation is mediated by a family of enzymes, termed hydrogenases, which either provide these organisms with reducing power from hydrogen oxidation, or act as electron sinks. There are two hydrogenases families that differ functionally from each other: NiFe hydrogenases tend to be more involved in hydrogen oxidation, while Iron-only FeFe (Fe only) hydrogenases in hydrogen production.

The localisation of iron hydrogenases can be cytoplasmic or periplasmic. Periplasmic iron hydrogenases in Desulfovibrio consists of a large subunit (HydA) and a small subunit (HydB) .
Moesin tail domain superfamily (Moesin_tail_sf)
Type: Homologous_superfamily

The ezrin-radixin-moesin (ERM) protein family link actin filaments of cell surface structures to the plasma membrane, using a C-terminal F-actin binding segment and an N-terminal FERM domain, a common membrane binding module . ERM proteins are highly related members of the larger protein 4.1 superfamily. The sole Drosophila ERM protein, Moesin, functions in maintaining epithelial integrity by regulating cell-signalling events that affect actin organisation and polarity .

This superfamily represents the actin-binding tail domain of ERM proteins.
Protease A inhibitor IA3 domain superfamily (IA3_dom_sf)
Type: Homologous_superfamily

This superfamily represents a domain found in N-terminal of IA3 protein (also known as Pai3).

The IA3 polypeptide of Saccharomyces cerevisiae (also known as Pai3) is an 8kDa inhibitor of the vacuolar aspartic proteinase (proteinase A or saccharopepsin, MEROPS peptidase family A1). It belongs to MEROPS inhibitor family I34, clan JA. No other aspartic proteinase has been found to be inhibited by IA3, and at least 15 aspartic proteinases related to YprA cleave IA3 as a substrate. Ligand- free IA3 has little intrinsic secondary structure, however, upon contact with proteinase A, residues 2-32 of the inhibitor become ordered and adopt a near perfect α-helical conformation occupying the active site cleft of the enzyme. This potent, specific interaction is directed primarily by hydrophobic interactions made by three key features in the inhibitory sequence .
Transglutaminase, C-terminal (Transglutaminase_C)
Type: Domain

Transglutaminases catalyse the post-translational modification of proteins at glutamine residues, with formation of isopeptide bonds. Members of the transglutaminase family usually have three domains: N-terminal (

), middle (

) and C-terminal. The middle domain is usually well conserved, but family members can display major differences in their N- and C-terminal domains, although their overall structure is conserved . This entry represents the C-terminal domain found in transglutaminases, which consists of an immunoglobulin-like β-sandwich consisting of seven strands in two sheets with a Greek key topology.

The best known transglutaminase is blood coagulation factor XIII, a plasma tetrameric protein composed of two catalytic A subunits and two non-catalytic B subunits. Factor XIII is responsible for cross-linking fibrin chains, thus stabilising the fibrin clot. Protein-glutamine gamma-glutamyltransferases (

) are calcium-dependent enzymes that catalyse the cross-linking of proteins by promoting the formation of isopeptide bonds between the γ-carboxyl group of a glutamine in one polypeptide chain and the ε-amino group of a lysine in a second polypeptide chain. TGases also catalyse the conjugation of polyamines to proteins .

Proteins containing this domain also include Protein 4.2 (also known as Epb42), which is one of the most abundant protein components of the erythrocyte membrane. The protein shares significant sequence homology with transglutaminases, but lacks the catalytic triad residues required for transglutaminase activity . The complete or nearly complete absence of protein 4.2 is associated with an atypical form of hereditary spherocytosis (HS) .
PapD-like superfamily (PapD-like_sf)
Type: Homologous_superfamily

The PapD-like superfamily of periplasmic chaperones directs the assembly of over 30 diverse adhesive surface organelles that mediate the attachment of many different pathogenic bacteria to host tissues, a critical early step in the development of disease. PapD, the prototypical chaperone, is necessary for the assembly of P pili. P pili contain the adhesin PapG, which mediates the attachment of uropathogenic Escherichia coli to Gal(alpha) Gal receptors present on kidney cells and are critical for the initiation of pyelonephritis. The PapD-like chaperones consist of two Ig-like domains oriented toward each other, forming L-shaped molecules. In the chaperone-subunit complex, the G1beta strand of the chaperone completes an atypical Ig fold in the subunit by occupying the groove and running parallel to the subunit C-terminal F strand. This donor strand complementation interaction simultaneously stabilises pilus subunits and caps their interactive surfaces, preventing their premature oligomerisation in the periplasm. During pilus biogenesis, the highly conserved N-terminal extension of one subunit has been proposed to displace the chaperone G1beta strand from its neighbouring subunit in a mechanism termed donor strand exchange .

This entry represents the immunoglobulin (Ig)-like β-sandwich domain found in PapD, as well as in other periplasmic chaperone proteins that include FimC and SfaE from E. coli, and Caf1m from Yersinia pestis . In addition, major sperm proteins (MSP) and other related sperm proteins (such as WR4 and SSP-19) contain an Ig-like domain with a similar structural fold to PapD . Major sperm proteins are central components in molecular interactions underlying sperm motility, with many isoforms existing in Caenorhabditis elegans.
Purple acid phosphatase-like, N-terminal (Purple_acid_Pase-like_N)
Type: Homologous_superfamily

Purple acid phosphatases (PAPs) are ubiquitous binuclear metal-containing acid hydrolases characterised by their acidic pH optima and their intense purple colour due to a TyrO-to-FeIII charge-transfer transition. The amino acid residues coordinating the metal ions are conserved in all PAPs. Active PAPs contain an FeIII ion coordinated to Tyr O, a His N, and an Asp O
2
, in addition to a divalent metal ion (Fe, Zn, or Mn) coordinated by a His N, a His N, and an Asn O. A hydroxide ion and an Asp O
2
bridge the two metal ions . These enzymes share a high degree of homology within their N-termini .

This entry also includes phospholipase D, the structure of which has been solved from Bacillus subtilis and shows a purple acid phosphatase-like fold .
Invasin/intimin cell-adhesion fragments (Invasin/intimin_cell_adhesion)
Type: Homologous_superfamily

Two types of pathogenic Escherichia coli, enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC), cause diarrhoeal disease by disrupting the intestinal environment through the intimate attachment of the bacteria to the intestinal epithelium. This process is mediated by intimin, an outer membrane protein that is homologous to the invasins of pathogenic Yersinia. EPEC and EHEC form characteristic lesions on infected mammalian cells called actin pedestals. Each of these two pathogens injects its own translocated intimin receptor (Tir) molecule into the plasma membranes of host cells. Interaction of translocated Tir with the bacterial outer membrane protein intimin is required to trigger the assembly of actin into focused pedestals beneath bound bacteria .
CBM2/CBM3, carbohydrate-binding domain superfamily (CBM2/CBM3_carb-bd_dom_sf)
Type: Homologous_superfamily

This carbohydrate-binding domain superfamily is found in a number of proteins, such as the chitobiase/beta-hexosaminidase family of glycoside hydrolases, bacterial cellulases and xylanases, and the bacterial scafoldin, cellobiose and cohesin proteins. The carbohydrate-binding domain consists of a β-sandwich formed of 9 strands in 2 sheets with a Greek-key topology and is a sub-class of the immunoglobin-like fold .
Adhesion domain superfamily (Adhesion_dom_sf)
Type: Homologous_superfamily

The bacterial adhesion domain is found in adhesin proteins, which form part of the adhesive pilus found on the cell surface. Adhesin proteins are important for receptor binding to host cells during pathogenesis. For example, the Escherichia coli PapG adhesin at the tip of the P pilus is necessary for attachment to the human kidney receptor during pyelonephritis pathogenesis . The bacterial adhesion domain consists of a β-sandwich formed of 9 strands in 2 sheets with a Greek-key topology and is a sub-class of the immunoglobin-like fold. Members of this structural superfamily include:

Collagen-binding domain of adhesion .

Fibrinogen-binding domain, which is found in both fibrinogen-binding adhesion SdrG and in clumping factor A; these proteins contain a duplication of this domain, where each copy of this fold displays a variation in the core structure .

Pilus subunits, such as mannose-specific adhesion FimH (duplication of this domain), PapK pilus subunit (similar to C-terminal domain of FimH), PapE pilus subunit, and F1 capsule antigen Caf1 .

PapG adhesion receptor-binding domain .

F17c-type adhesions, such as fimbrail adhesion F17-AG lectin domain, and fimbrial lectin GafD .

Dr-family adhesion Afa-III .
p53-like transcription factor, DNA-binding domain superfamily (p53-like_TF_DNA-bd_sf)
Type: Homologous_superfamily

This domain superfamily is found in a number of transcription factors, including p53, NFATC, TonEBP, STAT-1, and NFkappaB, where it is responsible for DNA-binding. These transcription factors play diverse roles in the regulation of cellular functions: the p53 tumour suppressor upregulates the expression of genes involved in cell cycle arrest and apoptosis ; NFATC regulates the production of effector proteins involved in coordinating the immune response ; TonEBP regulates gene expression induced by osmotic stress and helps regulate intracellular volume during cell growth ; STAT-1 plays an important role in B lymphocyte growth and function ; and NFkappaB is involved in the inflammatory response . The DNA-binding domain acts to clamp, or in the case of TonEBP, encircle the DNA target in order to stabilise the protein-DNA complex . Protein interactions may also serve to stabilise the protein-DNA complex, for example in the STAT-1 dimer the SH2 (Src homology 2) domain in each monomer is coupled to the DNA-binding domain to increase stability . The DNA-binding domain consists of a β-sandwich formed of 9 strands in 2 sheets with a Greek-key topology. This structure is found in many transcription factors, often within the DNA-binding domain.
Carboxypeptidase-like, regulatory domain superfamily (CarboxyPept-like_regulatory)
Type: Homologous_superfamily

This domain superfamily identifies a number of eukaryotic carboxypeptidases, these include carboxypeptidase D, E (H), N, X, X2 and Z. These are metallopeptidases belong to MEROPS peptidase family M14 (clan MC), subfamily M14B.

Carboxypeptidase D (CPD) is a new B-type metallocarboxypeptidase that is membrane bound and has an acidic pH optimum. A hydrophobic region at the N terminus represents the signal peptide, and one near the C terminus that probably represents the transmembrane anchor. A regulatory domain within the protein has been identified as a β-sandwich, comprising 7 strands in 2 sheets in a greek-key topology. Some family members have an additional 1-2 strands to the common fold .

The bacterial and archaeal sequences having this signature are variously annotated, examples are:

Hypothetical/conserved/membrane/cell surface protein

N-acetylglucosamine deacetylase

Side tail fibre protein homologue from lambdoid prophage Rac

Hypothetical tonB-linked outer membrane receptor

OmpA-related protein

Putative outer membrane protein, probably involved in nutrient binding

TonB-dependent receptor

This entry also includes the teneurin family members, which may function as cellular signal transducers.
HSP40/DnaJ peptide-binding (HSP40/DnaJ_pept-bd)
Type: Homologous_superfamily

The Escherichia coli Hsp40 DnaJ and Hsp70 DnaK cooperate in the binding of proteins at intermediate stages of folding, assembly, and translocation across membranes . Binding of protein substrates to the DnaK C-terminal domain is controlled by ATP binding and hydrolysis in the N-terminal ATPase domain. The interaction of DnaJ with DnaK is mediated at least in part by the highly conserved N-terminal J-domain of DnaJ. The J-domain interaction is localized to the ATPase domain of DnaK and is likely to be dominated by electrostatic interactions. J-domain may tether DnaK to DnaJ-bound substrates, which DnaK then binds with its C-terminal peptide-binding domain. The peptide-binding domain of DnaJ is comprised of a β sandwich made up of 6 β-strands divided into 2 sheets.
Cupredoxin (Cupredoxin)
Type: Homologous_superfamily

Copper is one of the most prevalent transition metals in living organisms and its biological function is intimately related to its redox properties. Since free copper is toxic, even at very low concentrations, its homeostasis in living organisms is tightly controlled by subtle molecular mechanisms. In eukaryotes, before being transported inside the cell via the high-affinity copper transporters of the CTR family, the copper (II) ion is reduced to copper (I). In blue copper proteins such as Cupredoxin, the copper (I) ion form is stabilised by a constrained His2Cys coordination environment.

This entry represents cupredoxin proteins, as well as structural homologues to cupredoxin. Structurally, the cupredoxin-like fold consists of a β-sandwich with 7 strands in 2 β-sheets, which is arranged in a Greek-key β-barrel . Some of these proteins have lost the ability to bind copper. Proteins with a cupredoxin-type fold are found in the following family groups:

Mono-domain cupredoxins, such as amicyanin, plastocyanin, pseudoazurin, plantacyanin, azurin, auracyanin, rusticyanin, stellacyanin, and mavicyanin.

Multi-domain cupredoxins, such as nitrite reductase (2 domains of this fold), multicopper oxidase CueO, spore coat protein A, ascorbate oxidase (3 domains of this fold), laccase (3 domains of this fold), ceruloplamin (6 domains of this fold), and coagulation factor V.

Red copper protein nitrocyanin and the C-terminal of nitrous oxide reductase.

Quinol oxidase and the periplasmic domain of cytochrome c oxidase subunit II.

Ephrin-a5 and ephrin-b2 ectodomain, which are related to cupredoxins but lack the metal-binding site.

The N-terminal domain of protein arginine deiminase Pad1-4 and Pad6, related to cupredoxin but lack the metal-biding site.
TRAF-like (TRAF-like)
Type: Homologous_superfamily

The tumour necrosis factor receptor (TNFR) associated factors (TRAFs) act as signal transducers for both TNFRs and interleukin-1/Toll-like receptors. TRAFs function in immunity, embryonic development, stress response and bone metabolism through their induction of cell proliferation, differentiation, and apoptosis . TRAFs are characterised by two domains: an N-terminal domain containing RING and zinc finger motifs that is essential for the activation of downstream effectors, and a C-terminal TRAF domain that is essential for self-association and receptor interaction . The TRAF-domain like fold is a β-sandwich consisting of 8 strands in 2 β-sheets and has a circularly permuted greek-key immunoglobulin-fold topology that contains an extra strand.

The substrate-binding domain (SBD) of the SIAH (seven in absentia homologue) family of proteins is structurally highly similar to the TRAF domain. The SIAH SBD interacts with a number of proteins, and is involved in TNF-alpha-mediated NFkappaB activation .
PHM/PNGase F domain superfamily (PHM/PNGase_F_dom_sf)
Type: Homologous_superfamily

Peptidyl-glycine alpha-amidating monooxygenase (PAM) is involved in the amidation of of bioactive peptides. It has two enzymatically active domains with catalytic activities -peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL), each of which binds one copper atom .
HSP20-like chaperone (HSP20-like_chaperone)
Type: Homologous_superfamily

This homologous superfamily represents HSP20-like chaperones and related proteins. Hsp20 is a mammalian small heat-shock protein family that occurs most abundantly in skeletal muscle and heart. It has a tendency to form dimers, via a disulphide linkage formed by an N-terminal cysteine, low heat stability and a poor chaperoning ability in comparison with other family members. Structurally, this and related proteins contain a β-sandwich fold consisting of 8 strands in two β-sheets in a greek-key topology .
Galactose-binding-like domain superfamily (Galactose-bd-like_sf)
Type: Homologous_superfamily

Proteins containing a galactose-binding-like domain fold can be found in several different protein families, in both eukaryotes and prokaryotes. The common function of these domains is to bind to specific ligands, such as cell-surface-attached carbohydrate substrates for galactose oxidase and sialidase , phospholipids on the outer side of the mammalian cell membrane for coagulation factor Va , membrane-anchored ephrin for the Eph family of receptor tyrosine kinases , and a complex of broken single-stranded DNA and DNA polymerase beta for XRCC1 .

The structure of the galactose-binding-like domain members consists of a β-sandwich, in which the strands making up the sheets exhibit a jelly roll fold. There is a high degree of similarity in the β-sandwich and in the loops between different family members, despite an often low level of sequence similarity.
Viral capsid/haemagglutinin protein (Capsid_hemagglutn)
Type: Homologous_superfamily

Representatives of this viral protein domain are found in the vp7 capsid protein of Bluetongue virus , and African horsesickness virus , the vp6 capsid protein of Bovine rotavirus , and in the haemagglutinin protein of various influenza viruses .

The vp7 and vp6 capsid proteins each consist of two domains, one a β sandwich, and the other an α helical bundle. The β sandwich domain described here is structurally very similar in vp6 and vp7, and may be involved in the attachment of the virus to the cell. In influenza A and B viruses, the haemagglutinin membrane glycoprotein serves to recognise the cell surface receptor sialic acid, and this domain forms the head region. In influenza C virus, a single multifunctional glycoprotein, the haemagglutinin-esterase-fusion protein, possesses a haemagglutinin domain, which recognises the cell surface receptor 9-O-acetylsialic acid, and bears strong structural resemblance to the haemagglutinin protein of influenza A and B viruses, as well as to the vp6 and vp7 capsid proteins. In each case, the domain consists of a β-sandwich, in which the strands making up the sheets exhibit a jellyroll fold. The resultant proteins form trimers.
F-MuLV receptor-binding (FMuLV_rcpt-bd)
Type: Homologous_superfamily

The F-MuLV receptor-binding domain forms part of the retroviral envelope glycoprotein in the murine leukaemia virus. Envelope glycoproteins are synthesized as single chain precursors, which are subsequently cleaved into the surface subunit (SU) and the transmembrane subunit TM. The N-terminal half of SU forms the receptor-binding domain (RBD), which is responsible for binding to the cell surface receptor, the cationic amino acid transporter mCAT-1. The RBD is structurally partitioned into a conserved β sandwich framework of Greek key topology and a variable helical loop subdomain . The RBD contains three variable regions, VRA, VRB and VRC, which vary in sequence and length between MuLVs that use different receptors. VRA and VRB are closely associated with one another in the helical subdomain. There is a putative receptor-binding pocket in VRA, which may play a role in helping to determine receptor specificity .
Adenovirus pIV-like, attachment domain (Adenovirus_pIV-like_att)
Type: Homologous_superfamily

The viral attachment protein domain forms part of the fibre proteins in adenoviruses , and the sigma 1 protein in reoviruses . Both proteins are trimers that contain fibrous tails and globular heads (reovirus), or knobs (adenovirus), which are structurally very similar. Both domain cores consist of eight anti-parallel β-sheets, forming either a β sandwich (fibre knob), or a β-barrel (sigma 1 head), with a long loop containing an α helix. The remaining loops tend to be longer in the fibre knob. Functionally both the fibre knob and the sigma 1 head are involved in binding selectively to cell surface receptors. The reoviruses bind JAM (junction adhesion molecule), while the adenoviruses use the CAR (Coxsackievirus and adenovirus) receptor, with the exception of subgroup B adenoviruses .