SII-SWORD/CoKE huggingface dataset:
Glypican (Glypican)
Type: Family

Glypicans are a family of heparan sulphate proteoglycans which are anchored to cell membranes by a glycosylphosphatidylinositol (GPI) linkage. Six members (GPC1-6) are known in vertebrates . The main function of glypicans is to regulate several signaling pathways, including those of Wnts, Hedgehogs, fibroblast growth factors and bone morphogenetic proteins (BMPs) .

Structurally, these proteins consist of three separate domains:

A signal sequence;

An extracellular domain of about 500 residues that contains 12 conserved cysteines probably involved in disulphide bonds and which also contains the sites of attachment of the heparan sulphate glycosaminoglycan side chains;

A C-terminal hydrophobic region which is post-translationally removed after formation of the GPI-anchor.
Trypanothione reductase (Trypnth_redctse)
Type: Family

Trypanothione reductase from Leishmania, and African and South American trypanosomes, has been purified and characterised . The enzymes have similar physical, mechanistic and kinetic properties, and are members of the flavoprotein disulphide oxidoreductase family. Trypanothione is the parasite analogue of glutathione, hence this enzyme is equivalent to glutathione reductase. It catalyses the reaction:

NADPH + trypanothione = NADP(+) + reduced trypanothione

Trypanothione reductase shows pronounced specificty for its disulphide substrates, trypanothione disulphide or glutathionylspermidine disulphide. The 3D structure of the enzyme has been determined and its mode of substrate binding revealed in detail , offering hope for the design of drugs to combat Chagas disease. The structure belongs to the α+β class, i.e. with mainly anti-parallel β-sheets separated by alpha and beta regions. It contains an α-β sandwich characteristic of FAD/NAD-linked reductases and a C-terminal dimerisation domain.
Small ribosomal subunit protein uS2 (Ribosomal_uS2)
Type: Family

This entry represents the family of ribosomal uS2 proteins. They are required for the assembly of different ribosomal subunits and are widely distributed among all living organisms .

Ribosomal uS2 family in humans includes three members:

Small ribosomal subunits uS2 (also known as RPSA).

Small ribosomal subunits uS2B (also known as RPSA2).

Small ribosomal subunits uS2m in mitochondria (also known as MRPS2).

Ribosomal protein SA (RPSA), previously named 37 kDa laminin receptor precursor/67 kDa laminin receptor (LRP/LR), has been characterised as a multifunctional protein that plays multiple roles in different pathological processes .

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Papillomavirus E2, N-terminal (PPV_E2_N)
Type: Domain

E2 is an early regulatory protein found in the dsDNA papillomaviruses. E2 regulates viral transcription and DNA replication. It binds to the E2RE response element (5'-ACCNNNNNNGGT-3') present in multiple copies in the regulatory region. It can either activate or repress transcription, depending on E2RE's position with regard to proximal promoter elements. Repression occurs by sterically hindering the assembly of the transcription initiation complex. The E1-E2 dimer complex binds to the origin of DNA replication .
OmpR/PhoB-type DNA-binding domain (OmpR/PhoB-type_DNA-bd)
Type: Domain

Bacteria and plants frequently use two-components signal transduction systems
(TCSs) to adapt to environmental changes and to survive under stress conditions. Typical TCSs couple a transmembrane histidine protein kinase (HK), which detects changes in the environmnent, to a cytosolic response regulator (RR), which often alters gene expression. Most RRs contain two distinct domains: an N-terminal receiver domain and a C-terminal effector domain. The former autophosphorylates on a histidine residue on detecting an external stimulus. The phosphate is then transferred to an invariant aspartate residue in a highly conserved receiver domain of the response regulator. Phosphorylation activates a variable effector domain of the response regulator, which triggers the cellular response. The C-terminal effector domain contains DNA and RNA polymerase binding sites. Several dimers or monomers bind head to tail to small tandem repeats upstream of the genes. The RNA polymerase binding sites interact with the alpha or sigma subunit of RNA polymerase. The OmpR/PhoB subfamily is the largest subfamily of RRs. Members of the OmpR/PhoB subfamily include such diverse transcriptional regulators as Escherichia coli PhoB (of the phosphate assimilation pathway), Enterococcus faecium VanR (which controls resistance to the antibiotic vancomycin), and Agrobacterium tumefaciens VirG (involved in the establishment of crown gall tumors in plant. The C-terminal effector domain of the OmpR/PhoB subfamily RRs binds DNA. This DNA-binding domain is also found in proteins other than response regulators, such as Vibrio cholerea ToxR, a transmembrane protein involved in cholera toxin expression .

The OmpR/PhoB-type DNA-binding domain has the typical fold of the winged
helix-turn-helix DNA-binding domain. The structure of the OmpR/PhoB-type DNA-
binding domain consists of three α-helices packed against two antiparallel
β-sheets, an N-terminal four-stranded antiparallel β-sheet and a C-
terminal hairpin. The hairpin interacts with a short stretch
of β-strand, that connects helices α1 and α2, to generate a three-
stranded antiparallel β-sheet. The topology for the domain is β1-β2-
β3-β4-α1-β5-α2-α3-β6-β7. The hydrophobic core of
the domain is formed by sidechains contributed by each of the seven β-strands and three α-helices .
Thiol-activated cytolysin (Thiol_cytolysin)
Type: Family

Thiol-activated cytolysins are toxins produced by a variety of Gram-positive bacteria and are characterised by their ability to lyse cholesterol-containing membranes, their reversible inactivation by oxidation and their capacity to bind to cholesterol. All these proteins contain a single cysteine residue, located in their C-terminal section, which has been shown to be essential for the binding to cholesterol.
B30.2/SPRY domain (B30.2/SPRY)
Type: Domain

The B30.2 domain was first identified as a protein domain encoded by an exon (named B30-2) in the Homo sapiens class I major histocompatibility complex region , whereas the SPRY domain was first identified in a Dictyostelium discoideum kinase splA and mammalian calcium-release channels ryanodine receptors . B30.2 domain consists of PRY and SPRY subdomains. The SPRY domains (after SPla and the RYanodine Receptor) are shorter at the N terminus than the B30.2 domains. The ~200-residue B30.2/SPRY (for B30.2 and/or SPRY) domain is present in a large number of proteins with diverse individual functions in different biological processes. The B30.2/SPRY domain in these proteins is likely to function through protein-protein interaction .
The N-terminal ~60 residues of B30.2/SPRY domains are poorly conserved and, as a consequence, a new domain name PRY was coined for a group of similar sequence segments N-terminal to the SPRY domains . The B30.2/SPRY domain contains three highly conserved motifs (LDP, WEVE and LDYE) . The B30.2/SPRY domain adopts a highly distorted, compact β-sandwich fold with two additional short β-helices at the N terminus. The β-sandwich of the B30.2/SPRY domain consists of two layers of β-sheets: sheet A composed of eight strands and sheet B composed of seven strands. All the β-strands are in antiparallel arrangement . The 5th β-strand corresponding to WEVE motif . Both the N- and C-terminal ends of the B30.2/SPRY domains in general are close to each other .
Epithelial sodium channel (ENaC)
Type: Family

The apical membrane of many tight epithelia contains sodium channels that are primarily characterised by their high affinity to the diuretic blocker
amiloride . These channels mediate the first step of active sodium
reabsorption essential for the maintenance of body salt and water homeostasis . In vertebrates, the channels control reabsorption of sodium in kidney, colon, lung and sweat glands; they also play a role in taste perception.

Members of the epithelial Na
+
channel (ENaC) family fall into four subfamilies, termed alpha, beta, gamma and delta . The proteins exhibit the same apparent topology, each with two transmembrane (TM) spanning segments, separated by a large extracellular loop. In most ENaC proteins studied to date, the extracellular domains are highly conserved and contain numerous cysteine residues, with flanking C-terminal amphipathic TM regions, postulated to contribute to the formation of the hydrophilic pores of the oligomeric channel protein complexes. It is thought that the well-conserved extracellular domains serve as receptors to control the activities of the channels.

Vertebrate ENaC proteins are similar to degenerins of Caenorhabditis elegans : deg-1, del-1, mec-4, mec-10 and unc-8. These proteins can be mutated to cause neuronal degradation, and are also thought to form sodium channels.

Structurally, the proteins that belong to this family consist of about 510 to 920 amino acid residues. They are made of an intracellular N terminus region followed by a transmembrane domain, a large extracellular loop, a second transmembrane segment and a C-terminal intracellular tail .
Dehydroquinase, class II (DHquinase_II)
Type: Family

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.
Death effector domain (DED_dom)
Type: Domain

The death effector domain (DED) is a homotypic protein interaction module composed of a bundle of six α-helices. DED is related in sequence and structure to the death domain (DD, see

) and the caspase recruitment domain (CARD, see

), which work in similar pathways and show similar interaction properties . The dimerisation of DED domains is mediated primarily by electrostatic interactions. DED domains can be found in isolation, or in combination with other domains. Domains associated with DED include: caspase catalytic domains (in caspase-8, -10), death domains (in FADD), nuclear localisation sequences (in DEDD), transmembrane domains (in Bap31 and Bar), nucleotide-binding domains (in Dap3), coiled-coil domains (in Hip and Hippi), SAM domains (in Bar), and E2-binding RING domains (in Bar) .

Several DED-containing proteins are involved in the regulation of apoptosis through their interactions with DED-containing caspases, such as caspases 8 and 10 in humans, both of which contain tandem pairs of DEDs. There are many DED-containing modulators of apoptosis, which can either enhance or inhibit caspase activation .
Zinc finger, RanBP2-type (Znf_RanBP2)
Type: Domain

This entry represents the zinc finger domain 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) , in Homo sapiens

, is a 358 kDa nucleoporin located on the cytoplasmic side of the nuclear pore complex which plays a role in nuclear protein import . RanBP2 contains multiple zinc fingers that mediate binding to RanGDP .

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.
Zinc finger, CCHC-type (Znf_CCHC)
Type: Domain

This entry represents the CysCysHisCys (CCHC) type zinc finger domains, and have the sequence:

C-X2-C-X4-H-X4-C

where X can be any amino acid, and number indicates the number of residues. These 18 residues CCHC zinc finger domains are mainly found in the nucleocapsid protein of retroviruses. It is required for viral genome packaging and for early infection process . It is also found in eukaryotic proteins involved in RNA binding or single-stranded DNA binding .

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.
GPCR, family 2, extracellular hormone receptor domain (GPCR_2_extracellular_dom)
Type: Domain

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The secretin-like GPCRs include secretin , calcitonin , parathyroid hormone/parathyroid hormone-related peptides and vasoactive intestinal peptide , all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.

This domain is found in the extracellular part of some of the secretin-like (family 2) GPCRs including the calcitonin receptor; corticotropin releasing factor receptor 1; diuretic hormone receptor; glucagon-like peptide 1 receptor; and parathyroid hormone peptide receptor.
EGF-like calcium-binding domain (EGF-like_Ca-bd_dom)
Type: Domain

A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been shown to be present in a large number of membrane-bound and extracellular, mostly animal, proteins. Many of these proteins require calcium for their biological function, and a calcium-binding site has been found at the N-terminal of some EGF-like domains . Calcium-binding may be crucial for numerous protein-protein interactions.

A common feature of all EGF-like domains is that they are found in the extracellular domain of membrane-bound proteins or in proteins known to be
secreted (exception: prostaglandin G/H synthase). The EGF-like domain includes six cysteine residues which have been shown to be involved in disulfide bonds. The structure of several EGF-like domains has been solved. The fold consists of two-stranded β-sheet followed by a loop to a C-terminal short
two-stranded sheet.

As in non-calcium binding EGF-like domains, there are six conserved cysteines and the structure of both types is very similar as calcium-binding induces only strictly local structural changes .

+------------------+ +---------+
| | | |
nxnnC-x(3,14)-C-x(3,7)-CxxbxxxxaxC-x(1,6)-C-x(8,13)-Cx
| |
+------------------+

'n': negatively charged or polar residue [DEQN]
'b': possibly beta-hydroxylated residue [DN]
'a': aromatic amino acid
'C': cysteine, involved in disulphide bond
'x': any amino acid.
Biotin-binding site (Biotin_BS)
Type: Binding_site

Biotin, which plays a catalytic role in some carboxyl transfer reactions, is covalently attached, via an amide bond, to a lysine residue in enzymes requiring this coenzyme . Sequence data reveal that the region around the biocytin (biotin-lysine) residue is well conserved and is evolutionary related to that around the lipoyl-binding lysine residue of 2-oxo acid dehydrogenase acyltransferases.