SII-SWORD/CoKE huggingface dataset:
SEA domain superfamily (SEA_dom_sf)
Type: Homologous_superfamily

The SEA domain has been named after the first three proteins in which it was identified (Sperm protein, Enterokinase and Agrin). The SEA domain has around 120 residues, it is an extracellular domain found in a number of cell surface and secreted proteins in which it could be present in one or two copies . Many SEA domains possess autoproteolysis activity. The SEA domain is closely associated with regions receiving extensive O-glycosylation and is present adjacent to the transmembrane segment in quite a number of type I transmembrane proteins on the cell surface, such as mucin-1 (MUC1) and Notch receptors and in type II single-pass transmembrane proteins such as enterokinase and matriptases. It also present in interphotoreceptor matrix proteoglycans (IMPG1 and IMPG2) . It has been proposed that carbohydrates are required to stabilise SEA domains and protect them against proteolytic degradation and that the extent of substitution may control proteolytic processing .

The SEA domain contains an about 80-residue conserved region and an about 40-residue segment that separates the conserved region from the subsequent C-terminal domains with an alternating conformation of β-sheets and α-helices. Structural analysis of MUC1 SEA domain revealed that it adopts a ferredoxin-like fold in which the cleavage site is located in the middle of the β-hairpin of the second and third β-strands. MUC1 SEA domain undergoes autoproteolysis at the glycine-serine peptide bond and the Ser responsible of this activity is located in the consensus motif GSXXX (X: a hydrophobic residue) .

Some proteins known to contain a SEA domain include:

Vertebrate agrin, an heparan sulfate proteoglycan of the basal lamina of the neuromuscular junction. It is responsible for the clustering of acetylcholine receptors (AChRs) and other proteins at the neuromuscular junction.

Mammalian enterokinase. It catalyses the conversion of trypsinogen to trypsin which in turn activates other proenzymes, including chymotrypsinogen, procarboxypeptidases, and proelastases.

63kDa sea urchin sperm protein (SP63). It might mediate sperm-egg or sperm-matrix interactions.

Animal perlecan, a heparan sulfate containing proteoglycan found in all basement membranes. It interacts with other basement membrane components such as laminin and collagen type IV and serves as an attachment substrate for cells.

Some vertebrate epithelial mucins. They form a family of secreted and cell surface glycoproteins expressed by epithelial tissues and implicated in epithelial cell protection, adhesion modulation and signaling.

Mammalian cell surface antigen 114/A10, an integral transmembrane protein that is highly expressed in hematopoietic progenitor cells and IL-3-dependent cell lines.
PGBD-like superfamily (PGBD-like_sf)
Type: Homologous_superfamily

This superfamily includes peptidoglycan binding domain (PGBD), as well as related domains that share the same structure. PGBD may have a general peptidoglycan binding function. It has a core structure consisting of a closed, three-helical bundle with a left-handed twist. It is found at the N or C terminus of a variety of enzymes involved in bacterial cell wall degradation . Examples are:

Muramoyl-pentapeptide carboxypeptidase (

)

N-acetylmuramoyl-L-alanine amidase cwlA precursor (cell wall hydrolase, autolysin,

)

Autolytic lysozyme (1,4-beta-N-acetylmuramidase, autolysin,

)

Membrane-bound lytic murein transglycosylase B

Zinc-containing D-alanyl-D-alanine-cleaving carboxypeptidase, VanX .

Many of the proteins having this domain are as yet uncharacterised. However, some are known to belong to MEROPS peptidase family M15 (clan MD), subfamily M15A metallopeptidases. A number of the proteins belonging to subfamily M15A are non-peptidase homologues as they either have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for the catalytic activity.

Eukaryotic enzymes can contain structurally similar PGBD-like domains. Matrix metalloproteinases (MMP), which catalyse extracellular matrix degradation, have N-terminal domains that resemble PGBD. Examples are gelatinase A (MMP-2), which degrades type IV collagen , stromelysin-1 (MMP-3), which plays a role in arthritis and tumour invasion , and gelatinase B (MMP-9) secreted by neutrophils as part of the innate immune defence mechanism . Several MMPs are implicated in cancer progression, since degradation of the extracellular matrix is an essential step in the cascade of metastasis .
PGBD superfamily (PGBDSf)
Type: Homologous_superfamily

This superfamily represents peptidoglycan binding domain (PGBD). PGBD may have a general peptidoglycan binding function. It has a core structure consisting of a closed, three-helical bundle with a left-handed twist. It is found at the N or C terminus of a variety of enzymes involved in bacterial cell wall degradation . Examples are:

Muramoyl-pentapeptide carboxypeptidase (

)

N-acetylmuramoyl-L-alanine amidase cwlA precursor (cell wall hydrolase, autolysin,

)

Autolytic lysozyme (1,4-beta-N-acetylmuramidase, autolysin,

)

Membrane-bound lytic murein transglycosylase B

Zinc-containing D-alanyl-D-alanine-cleaving carboxypeptidase, VanX .
Adenovirus DNA-binding, C-terminal domain superfamily (Ad_DBP_C_sf)
Type: Homologous_superfamily

The adenovirus early E2A DNA-binding protein (Ad DBP) is a multifunctional protein required, amongst other things, for DNA replication and transcription control. It binds to single- and double-stranded DNA, as well as to RNA, in a sequence-independent manner. AdDBP consists of two distinct domains. The C-terminal domain is highly conserved and possesses all the DNA binding properties .
Adenovirus DNA-binding, zinc binding domain superfamily (ADBP_zn-bd_sf)
Type: Homologous_superfamily

The adenovirus early E2A DNA-binding protein (Ad DBP) is a multifunctional protein required, amongst other things, for DNA replication and transcription control. It binds to single- and double-stranded DNA, as well as to RNA, in a sequence-independent manner. This signature represents the zinc binding domain of the viral DNA- binding protein, which is active in DNA replication. The zinc atoms appear to be required for the stability of the protein fold rather than being involved in direct contacts with the DNA, the protein contains two zinc atoms in different, novel coordinations. Two copies of this domain are found at the C terminus of many members of the family .
High potential iron-sulphur protein superfamily (HIPIP_sf)
Type: Homologous_superfamily

High potential iron-sulphur proteins (HiPIP) are a specific class of high-redox potential 4Fe-4S ferredoxins that functions in anaerobic electron transport and which occurs commonly in purple photosynthetic bacteria and in other bacteria, such as Paracoccus denitrificans and Thiobacillus ferrooxidans .

HiPIPs seem to react by oxidation of [4Fe-4S]2+ to [4Fe-4S]3+

The HiPIPs are small proteins which show significant variation in their sequences, their sizes (from 63 to 85 amino acids), and in their oxidation- reduction potentials. As shown in the following schematic representation the iron-sulphur cluster is bound by four conserved cysteine residues.

[4Fe-4S cluster]
| | | |
xxxxxxxxxxxxxxxxxxxCxCxxxxxxxCxxxxxCxxxx

'C': conserved cysteine involved in the binding of the iron-sulphur cluster.
Thiamin pyrophosphokinase, thiamin-binding domain superfamily (TPK_B1-bd_sf)
Type: Homologous_superfamily

Thiamin pyrophosphokinase (TPK,

) catalyzes the transfer of a pyrophosphate group from ATP to vitamin B1 (thiamin) to form the coenzyme thiamin pyrophosphate (TPP). Thus, TPK is important for the formation of a coenzyme required for central metabolic functions. The structure of thiamin pyrophosphokinase suggest that the enzyme may operate by a mechanism of pyrophosphoryl transfer similar to those described for pyrophosphokinases functioning in nucleotide biosynthesis .

TPK is a homodimer, and each subunit consists of two domains. One domain resembles a Rossman fold, while the other domain forms a β-sheet flattened sandwich structure containing a jelly-roll topology. The active site is located in a cleft at the dimer interface and is formed from residues from domains of both subunits. The thiamin binding site is primarily defined by the sandwich domain of one subunit and by a loop from the α-β domain of the other subunit . This superfamily describes the jelly-roll sandwich domain.
BEACH domain superfamily (BEACH_dom_sf)
Type: Homologous_superfamily

BEACH (Beige and Chediak-Higashi) domains, implicated in membrane trafficking, are present in a family of proteins conserved throughout eukaryotes. This group contains human lysosomal trafficking regulator (LYST), LPS-responsive and beige-like anchor (LRBA) and neurobeachin. Disruption of LYST leads to Chediak-Higashi syndrome, characterised by severe immunodeficiency, albinism, poor blood coagulation and neurologic problems. Neurobeachin is a candidate gene linked to autism. LBRA seems to be upregulated in several cancer types. It has been shown that the BEACH domain itself is important for the function of these proteins .

The BEACH domain is usually followed by a series of WD repeats.
Large ribosomal subunit protein bL17 superfamily (Ribosomal_bL17_sf)
Type: Homologous_superfamily

Large ribosomal subunit protein bL17 (also known as L17) is one of the proteins from the large ribosomal subunit. Bacterial L17 is a protein of 120 to 130 amino-acid residues while yeast YmL8 is twice as large (238 residues). The N-terminal half of YmL8 is collinear with the sequence of L17 from Escherichia coli.
Oxidoreductase, molybdopterin-binding domain superfamily (OxRdtase_Mopterin-bd_sf)
Type: Homologous_superfamily

A number of different eukaryotic oxidoreductases that require and bind a molybdopterin cofactor have been shown to share a few regions of sequence similarity. These enzymes include xanthine dehydrogenase (

), aldehyde oxidase (

), nitrate reductase (

), and sulphite oxidase (

). The multidomain redox enzyme NAD(P)H:nitrate reductase (NR) catalyses the reduction of nitrate to nitrite in a single polypeptide electron transport chain with electron flow from NAD(P)H-FAD-cytochrome b5-molybdopterin-NO(3). Three forms of NR are known, an NADH-specific enzyme found in higher plants and algae (

); an NAD(P)H-bispecific enzyme found in higher plants, algae and fungi (

); and an NADPH-specific enzyme found only in fungi (

) . The mitochondrial enzyme sulphite oxidase (sulphite:ferricytochrome c oxidoreductase;

) catalyses oxidation of sulphite to sulphate, using cytochrome c as the physiological electron acceptor. Sulphite oxidase consists of two structure/function domains, an N-terminal haem domain, similar to cytochrome b5; and a C-terminal molybdopterin domain .

This domain contains a three layers β-sheet structure and a β-grasp like motif.
Hemopexin-like domain superfamily (Hemopexin-like_dom_sf)
Type: Homologous_superfamily

Hemopexin (

) is a serum glycoprotein that binds haem and transports it to the liver for breakdown and iron recovery, after which the free hemopexin returns to the circulation . Hemopexin prevents haem-mediated oxidative stress. Structurally hemopexin consists of two similar halves of approximately two hundred amino acid residues connected by a histidine-rich hinge region. Each half is itself formed by the repetition of a basic unit of some 35 to 45 residues. Hemopexin-like domains have been found in two other types of proteins, vitronectin , a cell adhesion and spreading factor found in plasma and tissues, and matrixins MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, MMP-11, MMP-12, MMP-14, MMP-15 and MMP-16, members of the matrix metalloproteinase family that cleave extracellular matrix constituents . These zinc endopeptidases, which belong to MEROPS peptidase subfamily M10A, have a single hemopexin-like domain in their C-terminal section. It is suggested that the hemopexin domain facilitates binding to a variety of molecules and proteins, for example the HX repeats of some matrixins bind tissue inhibitor of metallopeptidases (TIMPs).
Ribulose bisphosphate carboxylase, large subunit, C-terminal domain superfamily (RuBisCO_lsu_C_sf)
Type: Homologous_superfamily

Ribulose bisphosphate carboxylase (RuBisCO) catalyses the initial step in Calvin's reductive pentose phosphate cycle in plants as well as purple and green bacteria. It catalyzes the primary CO2 fixation step. RuBisCO consists of a large catalytic unit and a small subunit of undetermined function. In plants, the large subunit is coded by the chloroplastic genome while the small subunit is encoded in the nuclear genome. Rubisco is activated by carbamylation of an active site lysine, stabilized by a divalent cation, which then catalyzes the proton abstraction from the substrate ribulose 1,5 bisphosphate (RuBP) and leads to the formation of two molecules of 3-phosphoglycerate .

The RuBisCo large subunit C-terminal domain has a TIM β/α-barrel fold.
Gp120 core superfamily (Gp120_core_sf)
Type: Homologous_superfamily

The envelope glycoprotein Gp160 of HIV1 and Simian immunodeficiency virus (SIV) is cleaved into the surface protein Gp120 and the transmembrane protein Gp41. This superfamily represents the Gp120 core .
FAS1 domain superfamily (FAS1_dom_sf)
Type: Homologous_superfamily

The FAS1 (fasciclin-like) domain is an extracellular module of about 140 amino acid residues. It has been suggested that the FAS1 domain represents an ancient cell adhesion domain common to plants and animals ; related FAS1 domains are also found in bacteria .

The crystal structure of FAS1 domains 3 and 4 of fasciclin I from Drosophila melanogaster (Fruit fly) has been determined, revealing a novel domain fold consisting of a seven-stranded β wedge and at least five α helices; two well-ordered N-acetylglucosamine groups attached to a conserved asparagine are located in the interface region between the two FAS1 domains . Fasciclin I is an insect neural cell adhesion molecule involved in axonal guidance that is attached to the membrane by a GPI-anchored protein.

FAS1 domains are present in many secreted and membrane-anchored proteins. These proteins are usually GPI anchored and consist of: (i) a single FAS1 domain, (ii) a tandem array of FAS1 domains, or (iii) FAS1 domain(s) interspersed with other domains.

Proteins known to contain a FAS1 domain include:

Fasciclin I (4 FAS1 domains).

Human TGF-beta induced Ig-H3 (BIgH3) protein (4 FAS1 domains), where the FAS1 domains mediate cell adhesion through an interaction with alpha3/beta1 integrin; mutation in the FAS1 domains result in corneal dystrophy .

Volvox major cell adhesion protein (2 FAS1 domains) .

Arabidopsis fasciclin-like arabinogalactan proteins (2 FAS1 domains) .

Mammalian stabilin protein, a family of fasciclin-like hyaluronan receptor homologues (7 FAS1 domains).

Human extracellular matrix protein periostin (4 FAS1 domains).

Bacterial immunogenic protein MPT70 (1 FAS1 domain) .

The FAS1 domains of both human periostin (

) and BIgH3 (

) proteins were found to contain vitamin K-dependent gamma-carboxyglutamate residues . Gamma-carboxyglutamate residues are more commonly associated with GLA domains (

), where they occur through post-translational modification catalysed by the vitamin K-dependent enzyme gamma-glutamylcarboxylase.
Alpha-amylase inhibitor superfamily (A-amylase_inhib_sf)
Type: Homologous_superfamily

Alpha-amylase inhibitor inhibits mammalian alpha-amylases specifically, by forming a tight stoichiometric 1:1 complex with alpha-amylase. The inhibitor has no action on plant and microbial alpha amylases.

A crystal structure has been determined for tendamistat, the 74-amino acid inhibitor produced by Streptomyces tendae that targets a wide range of mammalian alpha-amylases . The binding of tendamistat to alpha-amylase leads to the steric blockage of the active site of the enzyme. The crystal structure of tendamistat revealed an immunoglobulin-like fold that could potentially adopt multiple conformations. Such molecular flexibility could enable an induced-fit type of binding that would both optimise binding and allow broad target specificity.
Isochorismatase-like superfamily (Isochorismatase-like_sf)
Type: Homologous_superfamily

This entry represents a superfamily of hydrolase enzymes. Isochorismatase, also known as 2,3 dihydro-2,3 dihydroxybenzoate synthase catalyses the conversion of isochorismate, in the presence of water, to 2,3-dihydroxybenzoate and pyruvate (

).

The structure of isochorismatase has three layers (α/β/α) with parallel β-sheet of 6 strands.
Replication terminator Tus, domain 1 (Tus_dom1)
Type: Homologous_superfamily

Bacterial DNA replication terminus site-binding proteins (also known as Tus or Ter-binding proteins) are required for the termination of DNA replication and function by binding to DNA replication terminator sequences, thus preventing the passage of replication forks . The termination efficiency is affected by the affinity of a particular protein for the terminator sequence.

Tus protein folds into two domains divided by a central basic cleft . This superfamily describes the N-terminal 3-layer sandwich domain.
Guanylin superfamily (Guanylin_sf)
Type: Homologous_superfamily

This entry represents the guanylin superfamily. Its members include guanylate cyclase activator 2A and 2B. They are endogenous activators of intestinal guanylate cyclases.
Thrombospondin type-1 repeat superfamily (TSP1_rpt_sf)
Type: Homologous_superfamily

Thrombospondins are multimeric multidomain glycoproteins that function at cell surfaces and in the extracellular matrix milieu. They act as regulators of cell interactions in vertebrates. They are divided into two subfamilies, A and B, according to their overall molecular organisation. The subgroup A proteins TSP-1 and -2 contain an N-terminal domain, a VWFC domain, three TSP1 repeats, three EGF-like domains, TSP3 repeats and a C-terminal domain. They are assembled as trimer. The subgroup B thrombospondins, designated TSP-3, -4, and COMP (cartilage oligomeric matrix protein, also designated TSP-5) are distinct in that they contain unique N-terminal regions, lack the VWFC domain and TSP1 repeats, contain four copies of EGF-like domains, and are assembled as pentamers . EGF, TSP3 repeats and the C-terminal domain are thus the hallmark of a thrombospondin.

This repeat was first described in 1986 by Lawler and Hynes . It was found in the thrombospondin protein where it is repeated 3 times. Now a number of proteins involved in the complement pathway (properdin, C6, C7, C8A, C8B, C9) as well as extracellular matrix protein like mindin, F-spondin , SCO-spondin and even the circumsporozoite surface protein 2 and TRAP proteins of Plasmodium contain one or more instance of this repeat. It has been involved in cell-cell interaction, inhibition of angiogenesis and apoptosis .

The intron-exon organisation of the properdin gene confirms the hypothesis that the repeat might have evolved by a process involving exon shuffling . A study of properdin structure provides some information about the structure of the thrombospondin type I repeat .

The TSP1 repeat structure has a disulfide-rich fold with all-β sheets, each with three antiparallel strands.
Replication terminator Tus superfamily (Tus_sf)
Type: Homologous_superfamily

This superfamily includes bacterial DNA replication terminus site-binding proteins (also known as Tus or Ter-binding proteins). They are required for the termination of DNA replication and function by binding to DNA replication terminator sequences, thus preventing the passage of replication forks . The termination efficiency is affected by the affinity of a particular protein for the terminator sequence.

Structurally, the replication terminator Tus is contains a cluster of helices and a β-sandwich topology.
Ribulose bisphosphate carboxylase, small subunit superfamily (RuBisCO_ssu_sf)
Type: Homologous_superfamily

RuBisCO (ribulose-1,5-bisphosphate carboxylase/oxygenase) is a bifunctional enzyme that catalyses both the carboxylation and oxygenation of ribulose-1,5-bisphosphate (RuBP), thus fixing carbon dioxide as the first step of the Calvin cycle. RuBisCO is the major protein in the stroma of chloroplasts, and in higher plants exists as a complex of 8 large and 8 small subunits. The small subunits induce conformational changes in the large subunits enhancing its catalytic rate. Studies in Oryza sativa demonstrate that the availability of the small subunit upregulates the transcript levels of the large subunit . While the large subunit is coded for by a single gene, the small subunit is coded for by several different genes, which are distributed in a tissue specific manner. They are transcriptionally regulated by light receptor phytochrome , which results in RuBisCO being more abundant during the day when it is required.

The RuBisCo small subunit consists of a central four-stranded β-sheet, with two helices packed against it .
HscB, C-terminal domain superfamily (HscB_C_sf)
Type: Homologous_superfamily

This superfamily represents the C-terminal oligomerisation domain found in HscB (heat shock cognate protein B), which is also known as HSC20 (20K heat shock cognate protein) and J-protein Jac1 in yeast mitochondria . HscB acts as a co-chaperone to regulate the ATPase activity and peptide-binding specificity of the molecular chaperone HscA, also known as HSC66 (HSP70 class). HscB proteins contain two domains, an N-terminal J-domain, which is involved in interactions with HscA, connected by a short loop to the C-terminal oligomerisation domain; the two domains make contact through a hydrophobic interface. The core of the oligomerisation domain is thought to bind and target proteins to HscA and consists of an open, three-helical bundle . HscB, along with HscA, has been shown to play a role in the biogenesis of iron-sulphur proteins.
Neurohypophysial hormone domain superfamily (Neurhyp_horm_dom_sf)
Type: Homologous_superfamily

Oxytocin and vasopressin are nine-residue, structurally and functionally related neurohypophysial peptide hormones. Oxytocin mediates contraction of the smooth muscle of the uterus and mammary gland, while vasopressin has antidiuretic action on the kidney, and mediates vasoconstriction of the peripheral vessels . In common with most active peptides, both hormones are synthesised as larger protein precursors that are enzymatically converted to their mature forms. Members of this family are found in birds, fish, reptiles and amphibians (mesotocin, isotocin, valitocin, glumitocin, aspargtocin, vasotocin, seritocin, asvatocin, phasvatocin), in worms (annetocin), octopi (cephalotocin), Locusta migratoria (Migratory locust) (locupressin or neuropeptide F1/F2) and in molluscs (conopressins G and S) .
Winged helix-like DNA-binding domain superfamily (WH-like_DNA-bd_sf)
Type: Homologous_superfamily

Winged helix DNA-binding proteins share a related winged helix-turn-helix DNA-binding motif, where the "wings", or loops, are small β-sheets. The winged helix motif consists of two wings (W1, W2), three α-helices (H1, H2, H3) and three β-sheets (S1, S2, S3) arranged in the order H1-S1-H2-H3-S2-W1-S3-W2 . The DNA-recognition helix makes sequence-specific DNA contacts with the major groove of DNA, while the wings make different DNA contacts, often with the minor groove or the backbone of DNA. Several winged-helix proteins display an exposed patch of hydrophobic residues thought to mediate protein-protein interactions.

Many different proteins with diverse biological functions contain a winged helix DNA-binding domain, including transcriptional repressors such as biotin repressor, LexA repressor and the arginine repressor ; transcription factors such as the hepatocyte nuclear factor-3 proteins involved in cell differentiation, heat-shock transcription factor, and the general transcription factors TFIIE and TFIIF ; helicases such as RuvB that promotes branch migration at the Holliday junction, and CDC6 in the pre-replication complex ; endonucleases such as FokI and TnsA ; histones; and Mu transposase, where the flexible wing of the enhancer-binding domain is essential for efficient transposition .