SII-SWORD/CoKE huggingface dataset:
Outer surface protein C-like superfamily (OspC-like_sf)
Type: Homologous_superfamily

Members of this superfamily are lipoproteins that are probably involved in evasion of the host immune system by pathogens . Borrelia burgdorferi, the causative agent of Lyme disease, has the potential of producing more than 100 different lipoproteins that could become anchored to the outer membrane . One of these is outer surface protein C (OspC). OspC is a largely α-helical protein that forms a dimer with a characteristic central four-helical bundle formed by association of the two longest helices from each subunit .
Insulin-like superfamily (Insulin-like_sf)
Type: Homologous_superfamily

This entry represents a disulphide-rich α-helical domain found in insulin , as well as in related proteins, such as insulin-like growth factor , relaxin and bombyxin .

Insulin is found in many animals, and is involved in the regulation of normal glucose homeostasis. It also has other specific physiological effects, such as increasing the permeability of cells to monosaccharides, amino acids and fatty acids, and accelerating glycolysis and glycogen synthesis in the liver . Insulin exerts its effects by interaction with a cell-surface receptor, which may also result in the promotion of cell growth .

The insulin/IGF/relaxin superfamily is an ancient family of functionally diverse proteins . The 3D structures of a number of family members have been determined . The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of four cysteines in their A chain, the first of which is linked by a disulfide bond to the third, while the second and fourth are linked by interchain disulfide bonds to cysteines in the B chain.

This family includes:

Insulin and insulin-like proteins

Relaxin and prorelaxin

Insect prothoracicotropic hormone (bombyxin)

Insulin-like growth factors (IGF1 and IGF2)

Mammalian Leydig cell-specific insulin-like peptide (gene INSL3)

Invertebrates insulin-related peptides (IRPs)
Dockerin domain superfamily (Dockerin_dom_sf)
Type: Homologous_superfamily

Plant cell wall polysaccharides comprise the most abundant reservoir of organic carbon in the biosphere. The cellulosome is a large multienzyme
complex used by many anaerobic bacteria for the efficient degradation of plant-cell wall polysaccharides. The principal component of the cellulosome is a scaffolding subunit, a large enzyme-integrating protein, that contains cohesin modules (usually in multiple copies) for incorporation of the
different enzymes and other cellulosomal components. The enzymes contain a complementary type of module, the dockerin domain, that binds tenaciously to the cohesin modules of the scaffoldin subunit .

The dockerin domains consist of about 70 amino acid residues and contain two duplicated segments, each of about 22 amino acid residues. The first 12 residues of these duplicated sequences bear remarkable resemblance to the calcium-binding loop of the EF-hand motif, in which all the
calcium-binding residues (i.e., aspartic acids and asparagines) are highly conserved. The second halves of the duplicated sequences appear to form α helices. These helices would be analogous to the F helix of the EF-hand motif .

The dockerin domain comprises three α-helices. Helices H1 and H3, which are antiparallel to one another, and the two calcium-binding loops (Ca1 and Ca2) correspond to the tandem duplicated sequences that form the two F-hand motifs. A short loop region and helix H2 connect the F-hand motifs. The 12-residue Ca(2+)-binding loop of each motif coordinates one Ca2 ion in the typical pentagonal bipyramid configuration of EF-hand
Ca2-binding proteins .
Peptidase C15, pyroglutamyl peptidase I-like superfamily (Peptidase_C15-like_sf)
Type: Homologous_superfamily

This group of cysteine peptidases belong to MEROPS peptidase family C15 (pyroglutamyl peptidase I, clan CF). The type example being pyroglutamyl peptidase I of Bacillus amyloliquefaciens. There are similarities in structure between members of clan CF and members of three clans of metallopeptidases (MC, MF and MH) and all four are included in the same superfamily (phosphorylase/hydrolase-like fold) by the SCOP database. Members of clan CF have an α/β/α sandwich fold .

Pyroglutamyl peptidase I (also known as pyrrolidone carboxyl peptidase, Pcp or PYRase) is an exopeptidase that hydrolytically removes the pGlu from pGlu-peptides or pGlu-proteins . PYRase has been found in prokaryotes and eukaryotes where at least two different classes have been characterised: the first containing bacterial and animal type I PYRases, and the second containing animal type II and serum PYRases. Type I and bacterial PYRases are soluble enzymes, while type II PYRases are membrane-bound. The primary application of PYRase has been its utilisation for protein or peptide sequencing, and bacterial diagnosis . The conserved residues Cys-144 and His-168 have been identified by inhibition and mutagenesis studies .

Pyroglutamyl-peptidase 1-like protein belongs to the petidase C15 family, though its exact function is not known.
Dehydroquinase, class II superfamily (DHquinase_II_sf)
Type: Homologous_superfamily

3-dehydroquinate dehydratase (

), or dehydroquinase, catalyzes the conversion of 3-dehydroquinate into 3-dehydroshikimate. It is the third step in the shikimate pathway for the biosynthesis of aromatic amino acids from chorismate. Two classes of dehydroquinases exist, known as types I and II. Class-II enzymes are homododecameric enzymes of about 17kDa. They are found in some bacteria such as actinomycetales and some fungi where they act in a catabolic pathway that allows the use of quinic acid as a carbon source.

The dehydroquinase structure has a flavodoxin-like fold, which is composed of three layers (α/β/α) with parallel β-sheet of five strands.
ProQ/FinO domain superfamily (ProQ/FinO_sf)
Type: Homologous_superfamily

This entry represents a structural domain superfamily consisting of six helices in an irregular non-globular array; it also contains two small β-hairpins. This domain is found at the C terminus of the RNA-binding fertility inhibitor FinO that represses the conjugative transfer of F-like plasmids in Escherichia coli. FinO blocks the translation of TraJ, a positive activator of transcription of gene thereby protecting it from degradation, and catalyses FinP-TraJ mRNA hybridization. Interactions between these two RNAs are predicted to block the TraJ ribosomal binding site. FinO is largely helical, binds to its highest affinity binding site within FinP as a monomer, and contains two distinct RNA binding regions .

This domain superfamily is also found as an N-terminal domain in ProQ, a protein required for full activation of the osmoprotectant transporter ProP in Escherichia coli .
Zinc finger, RanBP2-type superfamily (Znf_RanBP2_sf)
Type: Homologous_superfamily

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

This entry represents the zinc finger domain superfamily found in RanBP2 proteins. Ran is an evolutionary conserved member of the Ras superfamily that regulates all receptor-mediated transport between the nucleus and the cytoplasm. Ran binding protein 2 (RanBP2) is a 358kDa nucleoporin located on the cytoplasmic side of the nuclear pore complex which plays a role in nuclear protein import . RanBP2 contains multiple zinc fingers which mediate binding to RanGDP .
Phospholipase A2 domain superfamily (PLipase_A2_dom_sf)
Type: Homologous_superfamily

Proteins containing this domain superfamily include eukaryotic and prokaryotic phospholipase A2 enzymes (PLA2;

), small lipolytic enzymes that releases fatty acids from the second carbon group of glycerol, usually in a metal-dependent reaction, to generate lysophospholipid (LysoPL) and a free fatty acid (FA) . The resulting products are either dietary or used in synthetic pathways for leukotrienes and prostaglandins. Often, arachidonic acid is released as a free fatty acid and acts as second messenger in signaling networks . These enzymes enable the of fatty acids and lysophospholipid by hydrolysing the 2-ester bond of 1,2-diacyl-3-sn-phosphoglycerides. In eukaryotes, PLA2 plays a pivotal role in the biosynthesis of prostaglandin and other mediators of inflammation. These enzymes are either secreted or cytosolic; the latter are either Ca dependent or Ca independent. Secreted PLA2s have also been found to specifically bind to a variety of soluble and membrane proteins in mammals, including receptors . As a toxin, PLA2 is a potent presynaptic neurotoxin which blocks nerve terminals by binding to the nerve membrane and hydrolyzing stable membrane lipids . The products of the hydrolysis (LysoPL and FA) cannot form bilayers leading to a change in membrane conformation and ultimately to a block in the release of neurotransmitters .
GPCR family 2, extracellular hormone receptor domain superfamily (GPCR_2_extracell_dom_sf)
Type: Homologous_superfamily

This domain superfamily is found in the extracellular part of some of the secretin-like (family 2) GPCRs including the corticotropin releasing factor receptor 1; calcitonin receptor; diuretic hormone receptor; glucagon-like peptide 1 receptor; and parathyroid hormone peptide receptor. The N-terminal extracellular domain is the major ligand recognition domain . This domain structure has a disulfide-rich all-β fold and contains a β sandwich of 5 strands.
Cobalamin adenosyltransferase-like superfamily (CblAdoTrfase-like_sf)
Type: Homologous_superfamily

ATP:cob(I)alamin (or ATP:corrinoid) adenosyltransferases (

), catalyse the conversion of cobalamin (vitamin B12) into its coenzyme form, adenosylcobalamin (AdoCbl)or coenzyme B12 . AdoCbl contains an adenosyl moiety liganded to the cobalt ion of cobalamin via a covalent Co-C bond. AdoCbl is required as a cofactor for the activity of certain enzymes.

ATP:cob(I)alamin adenosyltransferases are classed into three groups: CobA-type , EutT-type and PduO-type . Each of the three enzyme types appears to be specialised for particular AdoCbl-dependent enzymes or for the de novo synthesis AdoCbl. PduO and EutT are distantly related, sharing short conserved motifs, while CobA is evolutionarily unrelated and is an example of convergent evolution.

This entry represents a structural domain consisting of 4-helical bundle with a left-handed twist and one cross-over loop that goes across to a different side of the 4-helical bundle; there is no internal metal-binding site. This domain is found in EutT- and PduO-type ATP:cob(I)alamin adenosyltransferases. PduO functions to convert cobalamin to AdoCbl for 1,2-propanediol degradation , while EutT produces AdoCbl for ethanolamine utilisation . This domain is also found in the hypothetical protein Ta1238 from the archaeon Thermoplasma acidophilum .
Ribonucleoside hydrolase-like (Ribo_hydro-like)
Type: Homologous_superfamily

This entry represents the structural domain superfamily of ribonucleoside hydrolase. Nucleoside hydrolases are crucial for salvaging nucleic acid components in purine auxotrophic protozoan parasites, but are also present in higher eukaryotes and prokaryotes, where they could have a role in the metabolism of tRNA nucleosides . These enzymes are composed of three layers (α/β/α), consisting of a mixed eight-stranded β-sheet surrounded by six α-helices .
Glutamyl tRNA-reductase dimerization domain superfamily (GluRdtase_dimer_dom_sf)
Type: Homologous_superfamily

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway . The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin .

The first stage in tetrapyrrole synthesis is the synthesis of 5-aminoaevulinic acid ALA via two possible routes: (1) condensation of succinyl CoA and glycine (C4 pathway) using ALA synthase (

), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (

) to charge a tRNA with glutamate, glutamyl-tRNA reductase (

) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (

) to catalyse a transamination reaction to produce ALA.

The second stage is to convert ALA to uroporphyrinogen III, the first macrocyclic tetrapyrrolic structure in the pathway. This is achieved by the action of three enzymes in one common pathway: porphobilinogen (PBG) synthase (or ALA dehydratase,

) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase,

) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (

) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.

Uroporphyrinogen III is the first branch point of the pathway. To synthesise cobalamin (vitamin B12), sirohaem, and coenzyme F430, uroporphyrinogen III needs to be converted into precorrin-2 by the action of uroporphyrinogen III methyltransferase (

). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen III decarboxylase (

) .

This entry represents the helical dimerisation domain superfamily of glutamyl-tRNA reductase (

) . This enzyme reduces glutamyl-tRNA to glutamate-1-semialdehyde during the first stage of tetrapyrrole biosynthesis by the C5 pathway . The enzyme requires NADPH as a cofactor.
Amyloidogenic glycoprotein, heparin-binding domain superfamily (Amyloid_glyco_heparin-bd_sf)
Type: Homologous_superfamily

Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques . Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.

APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products . APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility . APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death . The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.

APP can be processed by different sets of enzymes:

In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling).

In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.

This superfamily represents a heparin-binding domain found at the N-terminal of the extracellular domain, which is itself found at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4). The core of the heparin-binding domain has an unusual disulphide-rich fold, consisting of a β-x-α-β-loop-β topology .
Polyribonucleotide nucleotidyltransferase, RNA-binding domain superfamily (PNPase_PH_RNA-bd_sf)
Type: Homologous_superfamily

This superfamily represents an RNA-binding domain found in bacterial and organelle PNPases, but not in exosomes. It usually occurs in combination with PH domain 1 (

) and PH domain 2 (

), both of which are found in PNPases and exosomes. The core structure of the RNA-binding domain consists of a DNA/RNA-binding 3-helical bundle.
PPM-type phosphatase-like domain superfamily (PPM-type-like_dom_sf)
Type: Homologous_superfamily

Protein phosphatases remove phosphate groups from various proteins that are the key components of a number of signalling pathways in eukaryotes and prokaryotes. Protein phosphatases that dephosphorylate Ser and Thr residues are classified into the phosphoprotein (PPP) and the protein phosphatase Mg2- or Mn2-dependent (PPM) families. The core structure of PPMs is the 300-residue PPM-type phosphatase domain that catalyses the dephosphorylation of phosphoserine- and phosphothreonine-containing protein. The PPM-type phosphatase domain is found as a module in diverse structural contexts and is modulated by targeting and regulatory subunits .

Some proteins known to contain a PPM-type phosphatase domain are listed below:

Bacillus subtilis stage II sporulation protein E (SpoIIE), controls the sporulation by dephosphorylating an anti-transcription factor SpoIIAA, reversing the actions of the SpoIIAB protein kinase in a process that is governed by the ADP/ATP ratio [levdikov].

Mycobacterium tuberculosis PP2C-family Ser/Thr phosphatase (PstP).

Eucaryotic PP2C, a negative regulator of protein kinase cascades that are activated as a result of stress.

Yeast adenylyl cyclase, plays essential roles in regulation of cellular metabolism by catalysing the synthesis of a second messenger, cAMP .

Mammalian mitochondrial pyruvate dehydrogenase phosphatase 1 (PDP1).

Plant kinase-associated protein phosphatase (KAPP), regulates receptor-like kinase (RLK) signalling pathways.

Plant absissic acid-insenstive 1 and 2 (ABI1 and ABI2), play a key absissic acid (ABA) signal transduction.

The PP2C-type phosphatase domain consists of 10 segments of β-strands and 5 segments of α-helix and comprises a pair of detached subdomains. The first is a small β-sandwich with strand β1 packed against strands β2 and β3; the second is a larger β-sandwich in which a four-stranded β-sheet packs against a three-stranded β-sheet with flanking α-helices .
Sodium:dicarboxylate symporter superfamily (Na:dicarbo_symporter_sf)
Type: Homologous_superfamily

It has been shown that integral membrane proteins that mediate the uptake of a wide variety of molecules with the concomitant uptake of sodium ions (sodium symporters) can be grouped, on the basis of sequence and functional similarities into a number of distinct families. One of these families is known as the sodium:dicarboxylate symporter family (SDF) .

Such re-uptake of neurotransmitters from the synapses, is thought to be an important mechanism for terminating their action, by removing these chemicals from the synaptic cleft, and transporting them into presynaptic nerve terminals, and surrounding neuroglia. This removal is also believed to prevent them accumulating to the point of reaching neurotoxic .

The structure of these transporter proteins has been variously reported to contain from 8 to 10 transmembrane (TM) regions, although 10 now seems to be the accepted value.

Members of the family include: several mammalian excitatory amino acid transporters, and a number of bacterial transporters. They vary with regards to their dependence on transport of sodium, and other ions.
Viral capsid core domain supefamily, Hepatitis B virus (Viral_capsid_core_dom_sf_HBV)
Type: Homologous_superfamily

This entry represent the core domain superfamily of the viral capsid (HBcAg) from various Hepatitis B virus (HBV), which is a major human pathogen. The virus is composed of an outer envelope of host-derived lipid containing the surface proteins, and an inner protein capsid that contains genomic DNA. The capsid is composed of a single polypeptide, HBcAg, also known as the core antigen. The capsid has a 5-helical fold, where two long helices form a hairpin that dimerises into a 4-helical bundle ; this fold is unusual for icosahedral viruses. The monomer fold is stabilised by a hydrophobic core that is highly conserved among human viral variants. The capsid is assembled from dimers via interactions involving a highly conserved arginine-rich region near the C terminus. This viral capsid acts as a core antigen, the major immunodominant region lying at the tips of the α-helical hairpins that form spikes on the capsid surface.