SII-SWORD/CoKE huggingface dataset:
Vitamin D-binding protein (VitD-bd)
Type: Family

A number of serum transport proteins are known to be evolutionarily related, including albumin, alpha-fetoprotein, vitamin D-binding protein and afamin . Albumin is the main protein of plasma; it binds water, cations (such as Ca
2+
, Na
+
and K
+
), fatty acids, hormones, bilirubin and drugs - its main function is to regulate the colloidal osmotic pressure of blood. Alphafeto- protein (alpha-fetoglobulin) is a foetal plasma protein that binds various cations, fatty acids and bilirubin. The biological role of afamin (alpha-albumin) has not yet been characterised. Vitamin D-binding protein (DBP) is an abundant serum glycoprotein secreted by the liver; the protein transports vitamin D sterols, binds to actin, and is found on the surface of B-lymphocytes and subpopulations of T-lymphocytes . The full length DBP contains 476-amino acids, including a 16-amino acid signal sequence. Sequence analysis reveals 23% similarity to albumin and to alpha-fetoprotein . DBP contains a characteristic placement of cysteine residues, identical to that in albumin, suggesting a similar folding structure. Albumin and alpha-fetoprotein contain three internally repeated domains . DBP shows similarity to the first two domains and has a truncated third domain, supporting the view that DBP is a member of the albumin/alpha-fetoprotein multigene family . Within the sequence, regularly-spaced disulphide bridges generate a 3-domain folding structure, each domain containing ~170 amino acids, with 5 or 6 internal disulphide bonds, as shown schematically below:

+---+ +----+ +-----+
| | | | | |
xxCxxxxxxxxxxxxxxxxCCxxCxxxxCxxxxxCCxxxCxxxxxxxxxCxxxxxxxxxxxxxxCCxxxxCxxxx
| | | | | |
+-----------------+ +-----+ +---------------+
Serpin family (Serpin_fam)
Type: Family

Protein protease inhibitors constitute a very important mechanism for regulating proteolytic activity. Serpins (SERine Proteinase INhibitors) belong to MEROPS inhibitor family I4, clan ID. Most serpin family members are indeed serine protease inhibitors, but several have additional cross-class inhibition functions and inhibit cysteine protease family members such as the caspases and cathepsins . Others, such as ovalbumin, are incapable of protease inhibition and serve other functions .
Tubulin (Tubulin)
Type: Family

Microtubules are polymers of tubulin, a dimer of two 55kDa subunits, designated alpha and beta . Within the microtubule lattice, α-β heterodimers associate in a head-to-tail fashion, giving rise to microtubule polarity. Fluorescent labelling studies have suggested that tubulin is oriented in microtubules with beta-tubulin toward the plus end .

For maximal rate and extent of polymerisation into microtubules, tubulin requires GTP. Two molecules of GTP are bound at different sites, termed N and E. At the E (Exchangeable) site, GTP is hydrolysed during incorporation into the microtubule. Close to the E site is an invariant region rich in glycine residues, which is found in both chains and is thought to control access of the nucleotide to its binding site .

Most species, excepting simple eukaryotes, express a variety of closely-related alpha- and beta-isotypes. A third family member, gamma tubulin, has also been identified in a number of species. Gamma tubulin is found at microtubule-organising centres, such as the spindle poles or the centrosome,
suggesting that it is involved in minus-end nucleation of microtubule assembly . Further eukaryotic tubulins (gamma, epsilon, zeta) that are restricted to certain lineages or species have been reported .

Bacterial and archaeal homologues of tubulin have been discovered. BtubA and BtubB, two bacterial homologues in the genus Prosthecobacter, have probably been derived by horizontal gene transfer .
Large ribosomal subunit protein uL14 (Ribosomal_uL14)
Type: Family

This entry represents the large ribosomal subunit protein uL14 (formerly known as L14) from all domains of life. In eubacteria, uL14 is known to bind directly to the 23S rRNA. It belongs to a family of ribosomal proteins, which have been grouped on the basis of sequence similarities. Based on amino-acid sequence homology, it is predicted that ribosomal protein L14 is a member of a recently identified family of structurally related RNA-binding proteins . L14 is a protein of 119 to 137 amino-acid residues.

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 .
Dbl homology domain (DH_dom)
Type: Domain

The Rho family GTPases Rho, Rac and CDC42 regulate a diverse array of cellular processes. Like all members of the Ras superfamily, the Rho proteins cycle between active GTP-bound and inactive GDP-bound conformational states. Activation of Rho proteins through release of bound GDP and subsequent binding of GTP, is catalysed by guanine nucleotide exchange factors (GEFs) in the Dbl family. The proteins encoded by members of the Dbl family share a common domain, presented in this entry, of about 200 residues (designated the Dbl homology or DH domain) that has been shown to encode a GEF activity specific for a number of Rho family members. In addition, all family members possess a second, shared domain designated the pleckstrin homology (PH) domain (

). Trio and its homologue UNC-73 are unique within the Dbl family insomuch as they encode two distinct DH/PH domain modules. The PH domain is invariably located immediately C-terminal to the DH domain and this invariant topography suggests a functional interdependence between these two structural modules. Biochemical data have established the role of the conserved DH domain in Rho GTPase interaction and activation, and the role of the tandem PH domain in intracellular targeting and/or regulation of DH domain function. The DH domain of Dbl has been shown to mediate oligomerisation that is mostly homophilic in nature. In addition to the tandem DH/PH domains Dbl family GEFs contain diverse structural motifs like serine/threonine kinase, RBD, PDZ, RGS, IQ, REM, Cdc25, RasGEF, CH, SH2, SH3, EF, spectrin or Ig.

The DH domain is composed of three structurally conserved regions separated by more variable regions. It does not share significant sequence homology with other subtypes of small G-protein GEF motifs such as the Cdc25 domain and the Sec7 domain, which specifically interact with Ras and ARF family small GTPases, respectively, nor with other Rho protein interactive motifs, indicating that the Dbl family proteins are evolutionarily unique. The DH domain is composed of 11 α helices that are folded into a flattened, elongated α-helix bundle in which two of the three conserved regions, conserved region 1 (CR1) and conserved region 3 (CR3), are exposed near the centre of one surface. CR1 and CR3, together with a part of alpha-6 and the DH/PH junction site, constitute the Rho GTPase interacting pocket.
Protamine P1 (Protamine_P1)
Type: Family

Protamines are small, highly basic proteins, that substitute for histones in sperm chromatin during the haploid phase of spermatogenesis. They pack sperm DNA into a highly condensed, stable and inactive complex , creating a more hydrodynamic sperm head for efficient swimming and protects the DNA from UV radiation and DNA damage . These proteins bind nonspecifically to the DNA and use a multi-step process to loop the DNA . There are two different types of mammalian protamine, called P1 and P2. P1 has been found in all species studied, while P2 is sometimes absent . There seems to be a single type of avian protamine whose sequence is closely related to that of mammalian P1 . Sequence comparisons of vertebrate and invertebrate protamines show that the sequence, structure, and probably function of these proteins evolve independently in vertebrates and various invertebrate groups .
PPM-type phosphatase, divalent cation binding (PP2C_BS)
Type: Binding_site

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 Mg(2+)- or Mn(2+)-dependent (PPM) families. The core structure of PPMs is the 300-residue PPM-type phosphatase domain that catalyzes 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 .

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 .

This entry represents a conserved aspartate residue involved in divalent cation binding .
Peptidase S26A, signal peptidase I (Pept_S26A_signal_pept_1)
Type: Family

This group of serine peptidases belong to MEROPS peptidase family S26 (signal peptidase I family, clan SF), subfamily S26A.

At least 3 eubacterial leader peptidases are known: murein prelipoprotein peptidase, which cleaves the leader peptide from a component of the bacterial outer membrane; type IV prepilin leader peptidase; and the serine-dependent leader peptidase 1, which has the more general role of cleaving the leader peptide from a variety of secreted proteins and proteins directed to the periplasm and periplasmic membrane . Leader peptidase 1 is similar to the eukaryotic signal peptidase, although the bacterial protein is monomeric, while the eukaryotic protein is multimeric .

Mitochondria contain a similar two-subunit serine protease that removes leader peptides from nuclear- and mitochondrial-encoded proteins, which localise in the inner mitochondrial space . The catalytic residues of a number of these peptides have been identified as a serine/lysine dyad .
Armadillo (Armadillo)
Type: Repeat

This entry represents proteins that contain the Armadillo repeat mainly from eukaryotes. These proteins include: Vacuolar protein 8, Importins, Catenins, Junction plakoglobin and related proteins.

The armadillo (Arm) repeat is an approximately 40 amino acid long tandemly repeated sequence motif first identified in the Drosophila melanogaster segment polarity gene armadillo involved in signal transduction through wingless. Animal Arm-repeat proteins function in various processes, including intracellular signalling and cytoskeletal regulation, and include such proteins as beta-catenin, the junctional plaque protein plakoglobin, the adenomatous polyposis coli (APC) tumour suppressor protein, and the nuclear transport factor importin-alpha, amongst others . A subset of these proteins is conserved across eukaryotic kingdoms. In higher plants, some Arm-repeat proteins function in intracellular signalling like their mammalian counterparts, while others have novel functions . The 3-dimensional fold of an armadillo repeat is known from the crystal structure of beta-catenin, where the 12 repeats form a superhelix of α helices with three helices per unit . The cylindrical structure features a positively charged grove, which presumably interacts with the acidic surfaces of the known interaction partners of beta-catenin.
Angiotensinogen (Angiotensinogen)
Type: Family

Angiotensinogen is a component of the renin-angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance. It is also known as the renin substrate, and is a non-inhibitory member of the serpin family of proteinase inhibitors (MEROPS inhibitor family I4, clan ID, MEROPS identifier I04.953).

Angiotensinogen is catalytically cleaved by renin to produce angiotensin I in response to lowered blood pressure. Angiotensin converting enzyme (ACE), subsequently removes a dipeptide to produce angiotensin II, the physiologically active peptide, which functions in the regulation of volume and mineral balance of body fluids . Angiotensin I and angiotensin II can be further processed to generate angiotensin III, which stimulates aldosterone release , and angiotensin IV. Angiotensin 1-9 is cleaved from angiotensin-1 by ACE2 and can be further processed by ACE to produce angiotensin 1-7, angiotensin 1-5 and angiotensin 1-4 .

Angiotensinogen is synthesised in the liver and secreted in plasma . Angiotensinogen appears to be associated with a predisposition to essential hypertension; it is also associated with pregnancy-induced hypertension (pih) (preeclampsia), a heterogeneous disorder that complicates 5-7% of all pregnancies and remains a leading cause of maternal, foetal and neonatal morbidity and mortality .

The entry represents the full precursor sequence of angiotensinogen.
RNA 3'-terminal phosphate cyclase (RNA3'_term_phos_cyc)
Type: Family

RNA cyclases are a family of RNA-modifying enzymes that are conserved in eukaryotes, bacteria and archaea. Type 1 RNA 3'-terminal phosphate cyclases (

) catalyse the conversion of 3'-phosphate to a 2',3'-cyclic phosphodiester at the end of RNA:

ATP + RNA 3'-terminal-phosphate = AMP + diphosphate + RNA terminal-2',3'-cyclic-phosphate

The physiological function of the cyclase is not known, but the enzyme could be involved in the maintenance of cyclic ends in tRNA splicing intermediates or in the cyclisation of the 3' end of U6 snRNA .

A second subfamily of RNA 3'-terminal phosphate cyclases (type 2) that do not have cyclase activity have been identified in eukaryotes. They are localised to the nucleolus and are involved in ribosomal modification .
Nucleocapsid protein, arenaviridae (Nucleocapsid_arenaviridae)
Type: Family

Arenaviridae are single stranded RNA viruses. The arenaviridae S RNAs that have been characterised include conserved terminal sequences, an ambisense arrangement of the coding regions for the precursor glycoprotein (GPC) and nucleocapsid (N) proteins and an intergenic region capable of forming a base-paired "hairpin" structure. The mature glycoproteins that result are G1 and G2 and the N protein .

This family represents the nucleocapsid protein that encapsulates the viral ssRNA .
Large ribosomal subunit protein eL30 (Ribosomal_eL30)
Type: Family

This family represents the large ribosomal subunit protein eL30 family of proteins, which includes:

Mammalian eL30 .

Thermococcus celer eL30 .

Methanococcus vannielii eL30 .

Sulfolobus acidocaldarius eL30 .

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 .
Heat shock factor (HSF)-type, DNA-binding (HSF_DNA-bd)
Type: Domain

Heat shock factor (HSF) is a transcriptional activator of heat shock genes : it binds specifically to heat shock promoter elements, which are palindromic sequences rich with repetitive purine and pyrimidine motifs . Under normal conditions, HSF is a homo-trimeric cytoplasmic protein, but heat shock activation results in relocalisation to the nucleus . Each HSF monomer contains one C-terminal and three N-terminal leucine zipper repeats . Point mutations in these regions result in disruption of cellular localisation, rendering the protein constitutively nuclear . Two sequences flanking the N-terminal zippers fit the consensus of a bi-
partite nuclear localisation signal (NLS). Interaction between the N- and C-terminal zippers may result in a structure that masks the NLS sequences: following activation of HSF, these may then be unmasked, resulting in relocalisation of the protein to the nucleus . The DNA-binding component of HSF lies to the N terminus of the first NLS region, and is referred to as the HSF domain.
Cadherin, Y-type LIR-motif (Cadherin_Y-type_LIR)
Type: Domain

Cadherins (CADHs) are transmembrane glycoproteins vital in calcium-dependent cell-cell adhesion during tissue differentiation . CADHs also have a crucial role in epithelial-to-mesenchymal transition (EMT), involved in migration properties of tumour cells. CADH6 is an EMT marker in thyroid cancer that interacts with the ATG8 family members GABARAP, BNIP3 and BNIP3L restraining autophagy through LIR (LC3 Interacting Regions, also known as ATG8-interacting motifs, AIMs) domains, a common feature among many cadherin family members . LIRs are short-linear motifs (SLiMs) of autophagy receptors and adaptor proteins that facilitates the selective recruitment of autophagy substrates to the autophagosome. They are characterised by degenerated sequences with a four-residue core central sequence involved in ATG8-binding, with the W/Y/FxxL/I/V pattern. Based on the aromatic amino acid in position 1 they can be classified into W-type, Y-type and F-type . This entry includes three conserved LIR motifs of CADHs, which two are Y-type (YDxL/I) and one F-type (FKKL), while a fourth LIR (YGGV) is only present in CADH6 members .
Herpesvirus Glycoprotein B (Herpes_Glycoprot_B)
Type: Family

Glycoprotein B is an envelope glycoprotein that plays a role in host cell entry, cell to-cell virus transmission, and fusion of infected cells .
Small ribosomal subunit protein uS7 (Ribosomal_uS7)
Type: Family

This entry includes the small ribosomal subunit protein uS7, formerly referred to as 30S ribosomal proteins S7 (bacterial, archaeal, plastid, mitochondrial), and eukaryotic 40S ribosomal proteins S5 (cytoplasmic) . 30S ribosomal protein S7 contacts ribosomal proteins S9 and S11. It is also one of the primary rRNA binding proteins - it binds directly to 16S rRNA - where it nucleates assembly of the head domain of the 30S subunit . S7 is located at the subunit interface close to the decoding centre, where it has been shown to contact mRNA. It has also been shown to contact tRNA in both the P and E sites; it probably blocks exit of the E site tRNA.

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 .
Transactivation protein X (Transactivation_prot_X)
Type: Family

The Hepatitis B virus (HBV) X gene shares sequences with both the polymerase and precore genes, carries several regulatory signals critical to the replicative cycle, and its product has a transactivating function . The transactivating function is probably associated with a tumourigenic potential of HBx, since x gene sequences, encoding functional HBx, have been repeatedly found integrated into the genome of liver carcinoma cells .