SII-SWORD/CoKE huggingface dataset:
SEPARIN core domain (SEPARIN_core_dom)
Type: Domain

This entry represents the SEPARIN core domain.

In eukaryotic cells, replicated DNA strands remain physically connected until their segregation to opposite poles of the cell during anaphase. This "sister chromatid cohesion" is essential for the alignment of chromosomes on the mitotic spindle during metaphase. Cohesion depends on the multisubunit cohesin complex, which possibly forms the physical bridges connecting sisters. The separins (separases) cleave the Scc1p subunit of the cohesin complex, allowing the separation of sister chromatids in anaphase. Separins are highly conserved in all eukaryotes but have not been detected in prokaryotes .

All known separin homologues possess a conserved C-terminal "separin" domain. The separin core domain contains a conserved histidine and cyteine residue, which are hallmarks of cysteine proteases. These two residues are invariably surrounded by small residues (glycine or serine), and each is preceded by amino acid sequences that are predicted to form hydrophobic β sheets. This pattern is characteristic of cysteine endopeptidases of the CD clan, which includes caspases, legumains, gingipains, clostripains, anf GPI-anchor amidases. The histidine end cysteine residues are likely to form the separin domain's catalytic dyad . The separin core domain forms the peptidase C50 family.
DG-type SEA domain (SEA_DG_dom)
Type: Domain

This entry represents the DG-type SEA domain.

Dystroglycan (DG) is an integral membrane receptor linking the extracellular matrix (ECM) and cytoskeleton. Through widespread expression in a variety of cell types, including muscle, neural and epithelial cells, DG plays diverse and important roles in cell functions from basement membrane assembly to tissue morphogenesis and structural integrity. DG is encoded by a single gene and posttranslationally cleaved into two noncovalently associated subunits by autoproteolysis within a distinctive protein motif called an sea urchin- enterokinase-agrin (SEA) domain. The resulting heterodimer is composed of a transmembrane subunit that tethers to the cell surface an extracellular subunit bearing extensive O-linked glycosylation. O-linked glycosylation of the extracellular DG subunit (alpha-DG) mediates binding to several ECM ligands, including laminins and perlecan. The cleavage of DG elicits a conspicuous change in its ligand-binding activity. Extensive work has demonstrated the importance of alpha-DG glycosylation for DG functions and how altered alpha-DG glycosylation leads to receptor dysfunction with direct implications for human diseases. However, functions contained within the DG transmembrane subunit (beta-DG), and the roles of this subunit in human disease, are poorly understood . The DG-type SEA domain forms the peptidase S72 family.

The ~120-residue DG-type SEA domain is predicted to display a four-stranded antiparallel β sheet (beta1-beta4) backed by α helices (alpha1-alpha4). The cleavage occurs at a bend between the beta2 and beta3 sheets. The cleavage of the DG precursor requires the sequence GSIVV, where cleavage occurs between the glycine and serine .
Pestivirus NS2, peptidase C74 (NS2_C74)
Type: Domain

Pestiviruses are animal pathogens that are recognised as a separate genus of the family Flaviviridae. The pestiviral genome is a single-stranded RNA of positive polarity. It is translated into a large polyprotein, which is cotranslationally and posttranslationally processed by viral and cellular proteases. Pestivirus nonstructural protein 2 (NS2) is predicted to have a multidomain organisation. The C-terminal-most domain of NS2 is a cysteine autoprotease responsible for NS2-3 cleavage. The catalytic triad is formed by His, Glu, and Cys. The pestivirus NS2 protease domain contains five Cys and one His organised in a linear fashion, suggesting the presence of a mononuclear ZnB site . The pestivirus NS2 protease domain forms peptidase family C74.

The entry represents the entire pestivirus NS2 protease domain.
Sedolisin domain (Sedolisin_dom)
Type: Domain

This entry represents the sedolisin domain.

Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold ressembles that of subtilisin; however they are considerably larger, with the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad, Ser-Glu-Asp (SED in single-letter notation), as well as the presence of an aspartic acid residue in the oxyanion hole. Sedolisins are acid-acting endopeptidases or tripeptidyl peptidases. They are widely distributed among archea, bacteria, fungi, slime mold, amoeba and animal kingdom including amphibians, fish and mammals. Sedolisins form peptidase family S53 of the subtilisin-like (SB) clan .

The three dimensional fold of sedolisin is based on a 7-stranded, all-parallel β-sheet. The sheet is flanked on both sides by several helices .

Some proteins known to contain a sedolisin domain are listed below:

Pseudomonas sedolisin.

Xanthomonas sp. Xanthomonalisin.

Bacterial kumamolisin.

Aspergillus oryzae aorsin.

Fungal sedolisin-B, a secreted tripeptidyl-peptidase which degrades proteins at acidic pHs and is involved in virulence.

Mammalian lysosomal tripeptidyl-peptidase 1 (TPP-1) or CLN2, involved in hydrolysis of hydrophobic proteins. A hereditary deficiency of human TPP-1 results in infantile neuronal ceroid lipofuscinosis (Batten disease), a rare but fatal neurodegenerative disorder.
Zinc finger and BTB domain-containing protein 40, BTB/POZ domain (ZBTB40_BTB_POZ_dom)
Type: Domain

The function of Zinc finger and BTB domain-containing protein 40 (ZBTB40) is not clear. It has been linked to the reduced hip bone mineral density (BMD) and the increased risk of hip osteoporosis .

This entry represents the N-terminal BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain of ZBTB40.
AT-rich interactive domain-containing protein 5B, ARID/BRIGHT DNA binding domain (ARID5B_ARID/BRIGHT_DNA-bd)
Type: Domain

This entry represents the AT-rich ARID/BRIGHT DNA binding domain of ARID5B.

ARID5B, also known as modulator recognition factor-2 (Mrf-2), is a member of the AT-rich interaction domain (ARID) family of transcription factors . Human ARID5B forms complex with PHF2, a jmjC demethylase; this complex serves as a signal-sensing modulator of histone methylation and gene transcription . It facilitates chondrogenesis by recruiting the histone demethylase PHF2 to Sox9-regulated genes . Mouse Mrf-2 is required for adipogenesis and to maintain normal functions in mature adipocytes .
Nuclear body protein Sp140, bromodomain (Sp140_Bromo)
Type: Domain

The function of nuclear protein Sp140 is not known, though it contains several chromatin related modules such as plant homeodomain (PHD), bromodomain (BRD) and SAND domain, which suggests a role in chromatin-mediated regulation of gene expression . It also harbours a nuclear localisation signal and a dimerisation domain (HSR or CARD domain). The PHD finger of Sp140 presents an atypical fold which does not bind to histone H3 tails but binds to peptidylprolyl isomerase Pin1. Pin1 catalyses the isomerisation of a phospho-Threonine-Proline bond in Sp140-PHD and thus may modulate Sp140 function .

Human Sp140 is an interferon inducible nuclear leukocyte-specific protein that may be involved in the pathogenesis of acute promyelocytic leukemia and viral infection . It localises to LYSP100-associated nuclear dots and is also a component of the promyelocytic leukemia nuclear body (PML-NBs) . The Sp140 locus has been identified as a lymphocytic leukemia (CLL) risk locus . This entry also includes protein Sp140-like (SP140L) which acts as an autoantigen in primary biliary cirrhosis patients .
Membrane-spanning 4-domains subfamily A (MS4A)
Type: Family

Membrane-spanning four-domains subfamily A (MS4A) includes B-cell-specific antigen CD20 (MS4A1), high affinity immunoglobulin epsilon receptor beta chain (MS4A2), hematopoietic-cell-specific protein HTm4 (MS4A3), and related proteins. These proteins share a similar structure with four transmembrane domains and have amino acid identities of 25-40% . They are predominantly expressed in hematopoietic cells, but some can be found in other tissues including testis and brain .

MS4A1 (B-lymphocyte antigen CD20) , MS4A2 (high affinity IgE receptor subunit beta) , and MS4A4B have been shown to have an important role in immunity.

Several variants within the MS4A gene cluster have been implicated in Alzheimer's disease .
Sarcospan (Sarcospan)
Type: Family

Sarcospan is a transmembrane component of dystrophin-glycoprotein complex (DGC), a complex that spans the muscle plasma membrane and forms a link between the F-actin cytoskeleton and the extracellular matrix . The DGC is composed of distinct subcomplexes; sarcospan preferentially associates with the sarcoglycan subcomplex . Loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy. The role of the sarcoglycan complex and sarcospan is thought to be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton .
Endosomal transmembrane epsin interactor 1-3 (ENTREP1-3)
Type: Family

This family includes Endosomal transmembrane epsin interactor 1/2/3, also known as FAM189 (family with sequence similarity 189). ENTREP1 functions as an activator of the E3 ubiquitin protein ligase ITCH in the ubiquitination of the CXCL12-activated CXCR4 receptor which triggers CXCR4 endocytosis and desensitization, negatively regulating the CXCL12/CXCR4 signaling pathway . COTE1 (FAM189B/ENTREP3) contributes to hepatocellular carcinoma tumourigenesis by regulating cell proliferation through modulating WWOX signalling .
Histone H3-K79 methyltransferase (H3-K79_meTrfase)
Type: Family

The enzymes that catalyse histone methylation are classified into 3 families: the PRMT (protein arginine N-methyltransferase) family, the SET-domain-containing family, and the non-SET domain proteins. Lysine 79 (K79) of H3 is methylated by a methyltransferase represented in this entry that lacks a SET domain .

H3K79 methylation occurs in a variety of organisms ranging from yeast to human. In budding yeast, K79 methylation is mediated by the silencing protein Dot1 . Dot1 homologues can be found in a variety of eukaryotic organisms; in mammals the homologous protein is called Dot1-like protein (DOT1L) . Dot1/DOT1L catalyses the sequential mono-, di-, and tri-methylation of H3K79, while SET domain-containing methyltransferases mediate methylation in a processive manner . K79 methylation level is regulated throughout the cell cycle and plays a critical role in the progression of G1 phase, S phase, mitosis, and meiosis .
Fork head domain conserved site 2 (TF_fork_head_CS_2)
Type: Conserved_site

The fork head domain is a conserved domain of about 100 amino-acid residues found in some eukaryotic transcription factors. It is involved in DNA-binding . This entry represents a conserved heptapeptide located in the central section of the domain.
ELO family, conserved site (ELO_CS)
Type: Conserved_site

This entry represents a conserved site found in the ELO (Elongation of fatty acids protein) family members, such as:

Mammalian proteins ELOVL1 (Elongation of very long chain fatty acids protein 1) to ELOVL4 . These proteins all seem to be involved in the synthesis of very long chain fatty acids.

Yeast ELO1, ELO2 and ELO3 . They seem to be components of membrane-bound fatty acid elongation systems.

Caenorhabditis elegans hypothetical protein C40H1.4.

Caenorhabditis elegans hypothetical protein D2024.3.

The proteins have from 271 to 435 amino acid residues. Structurally, they seem to be formed of three sections: a N-terminal region with two transmembrane domains, a central hydrophilic loop and a C-terminal region that contains from one to three transmembrane domains. This entry represents a conserved region that contains three histidines. This region is located in the hydrophilic loop.
Glycosyl hydrolases family 31, active site (Glyco_hydro_31_AS)
Type: Active_site

Glycoside hydrolase family 31

comprises enzymes with several known activities; alpha-glucosidase (

), alpha-galactosidase (

); glucoamylase (

), sucrase-isomaltase (

); isomaltase (

); alpha-xylosidase (

); alpha-glucan lyase (

).

The region around this active residue is highly conserved and is represented in this entry.
Glycosyl hydrolases family 31, conserved site (Glyco_hydro_31_CS)
Type: Conserved_site

Glycoside hydrolase family 31

comprises enzymes with several known activities; alpha-glucosidase (

), alpha-galactosidase (

); glucoamylase (

), sucrase-isomaltase (

); isomaltase (

); alpha-xylosidase (

); alpha-glucan lyase (

).

This entry represents a conserved site in proteins of the glycoside hydrolase family 31. It contains two conserved cysteines.
Centrosomal protein of 131kDa (CEP131)
Type: Family

Centrosomal protein of 131kDa (CEP131) is a cilium-specific protein required for cilium/flagellum formation . In Drosophila, CEP131, also known as Azi1, functions in ciliogenesis and is involved in genome stability and centriole duplication . In mice, it mediates trafficking events necessary for spermiogenesis and male fertility . It interacts with BBS4 (Bardet-Biedl syndrome 4) and regulates ciliary trafficking of the BBSome .
NEDD8-activating enzyme E1 catalytic subunit, N-terminal domain (Uba3_N)
Type: Domain

This group of proteins includes NEDD8-activating enzyme E1 catalytic subunit (Uba3) from fungi, plants and invertebrates. In budding yeasts, it is a catalytic subunit of the dimeric Uba3-Ula1 E1 enzyme that activates NEDD8/Rub1 before neddylation, the process by which the ubiquitin-like protein NEDD8 is conjugated to its target proteins . In C.elegans, Uba3 (also known as rfl-1) is required for cytokinesis and mitotic spindle orientation . In mammals, it down-regulates steroid receptor activity and is necessary for cell cycle progression .

This entry represents the N-terminal domain of Uba3.
UbiA prenyltransferase conserved site (UbiA_prenylTrfase_CS)
Type: Conserved_site

The following prenyltransferases are evolutionary related :

Bacterial 4-hydroxybenzoate octaprenyltransferase (gene ubiA).

Yeast mitochondrial para-hydroxybenzoate--polyprenyltransferase (gene COQ2).

Protoheme IX farnesyltransferase (heme O synthase) from yeast and mammals (gene COX10) and from bacteria (genes cyoE or ctaB).

These proteins probably contain seven transmembrane segments. The best conserved region is located in a loop between the second and third of these segments. It is represented by this entry.
Tissue factor, conserved site (Tissue_Factor_CS)
Type: Conserved_site

Tissue factor (TF) is an integral membrane glycoprotein that initiates blood coagulation by forming a complex with circulating factor VII or VIIa. The complex then activates factors IX or X by specific limited proteolysis.

The mature form of TF is a protein of about 250 amino acid residues. TF consists of an extracellular domain of about 210 residues that contains two disulfide bonds, followed by a transmembrane region and a short cytoplasmic C-terminal domain. This entry represents the region centred on the two cysteines involved in the first disulfide bond.
Interleukin-6/GCSF/MGF, conserved site (IL6/GCSF/MGF_CS)
Type: Conserved_site

The following cytokines can be grouped into a single family on the basis of sequence similarities.

Interleukin-6 (IL-6) (also known as B-cell stimulatory factor 2 (BSF-2) or interferon beta-2) is a cytokine that has a wide variety of biological functions. It plays an essential role in the final differentiation of B-cells into IG-secreting cells, as well as inducing myeloma/plasmacytoma growth, nerve cell differentiation and, in hepatocytes, acute phase reactants.

Granulocyte colony-stimulating factor (G-CSF) belongs to the cytokine family whose members regulate hematopoietic cell proliferation and differentiation. G-CSF exclusively stimulates the colony formation of granulocytes.

Myelomonocytic growth factor (MGF) is an avian hematopoeitic growth factor that stimulates the proliferation and colony formation of normal and transformed avian cells of the myeloid lineage.

These cytokines are glycoproteins of about 170 to 180 amino acid residues that contains four conserved cysteine residues involved in two disulfide bonds . This entry represents a site that contains the last two cysteines as well as other conserved residues.
Interleukin-6/GCSF/MGF (IL-6/GCSF/MGF)
Type: Family

Interleukin-6 (IL6), also refered to as B-cell stimulatory factor-2 (BSF-2) and interferon beta-2, is a cytokine involved in a wide variety of biological functions . It plays an essential role in the final differentiation of B-cells into IG-secreting cells, as well as inducing myeloma/plasmacytoma growth, nerve cell differentiation and, in hepatocytes, acute phase reactants .

A number of other cytokines may be grouped with IL6 on the basis of sequence similarity : these include granulocyte colony-stimulating factor (GCSF) and myelomonocytic growth factor (MGF). GCSF acts in hematopoiesis by affecting the production, differentiation and function of 2 related white cell groups in the blood . MGF also acts in hematopoiesis, stimulating proliferation and colony formation of normal and transformed avian cells of the myeloid lineage.
Ribonucleotide reductase small subunit, acitve site (RNR_small_AS)
Type: Active_site

Ribonucleotide reductase (

) catalyses the reductive synthesis of deoxyribonucleotides from their corresponding ribonucleotides. It provides the precursors necessary for DNA synthesis. Ribonucleotide reductase is an oligomeric enzyme composed of a large subunit (700 to 1000 residues) and a small subunit (300 to 400 residues).

The small chain binds two iron atoms (three Glu, one Asp, and two His are involved in metal binding) and contains an active site tyrosine radical. The regions of the sequence that contain the metal-binding residues and the active site tyrosine are conserved in ribonucleotide reductase small chain from prokaryotes, eukaryotes and viruses.

This entry represents a conserved region that contains the active site residue as well as a glutamate and a histidine involved in the binding of iron.
Pentaxin, conserved site (Pentaxin_CS)
Type: Conserved_site

Pentaxins (or pentraxins) are a family of proteins which show, under electron microscopy, a discoid arrangement of five noncovalently bound subunits. Proteins known to belong to this family are:

C-reactive protein (CRP), a protein which, in mammals, is expressed during acute phase response to tissue injury or inflammation. CRP displays several functions associated with host defense: it promotes agglutination, bacterial capsular swelling, phagocytosis and complement fixation through its calcium-dependent binding to phosphorylcholine. CRPs have also been sequenced in an invertebrate, the Atlantic horseshoe crab, where they are a normal constituent of the hemolymph.

Serum Amyloid P-component (SAP), a precursor of amyloid component P which is found in basement membrane and is associated with amyloid deposits.

Hamster female protein (FP), a plasma protein whose concentration is altered by sex steroids and stimuli that elicit an acute phase response.

A number of proteins, whose function is not yet clear, contain a C-terminal pentaxin-like domain. These proteins are:

Human PTX3 (or TSG-14). PTX3 is a cytokine-induced protein.

Guinea pig apexin , a sperm acrosomal protein. Apexin seems to be the ortholog of human neuronal pentraxin II (gene NPTX2) .

Rat neuronal pentaxin I .

The sequences of the different members of this family are quite conserved. This entry represents a six residue pattern which includes a cysteine known to be involved in a disulfide bridge in CRPs and SAP.
Interleukin-2, conserved site (IL-2_CS)
Type: Conserved_site

Interleukin-2 (IL-2) is a cytokine produced by T-helper cells in response to antigenic or mitogenic stimulation. This protein is required for T-cell proliferation and other activities crucial to the regulation of the immune response.

The mature form of IL-2, after cleavage of the signal sequence, is a glycoprotein of about 130 amino acids that contains a single disulfide bond. This conserved site includes the first cysteine involved in the disulfide bond.
Syndecan, conserved site (Syndecan_CS)
Type: Conserved_site

The syndecans are multifunctional transmembrane heparan sulphate bearing cell surface receptors . There are four syndecans in mammals (syndecan1-4), but only one syndecan in C. elegans or D. melanogaster. These homologues have similar protein structure that consists of four separate domains:

A signal sequence;

An extracellular domain (ectodomain) of variable length whose sequence is not evolutionary conserved in the various forms of syndecans. The ectodomain contains the sites of attachment of the heparan sulphate glycosaminoglycan side chains;

A transmembrane region;

A highly conserved cytoplasmic domain of about 30 to 35 residues, which could interact with cytoskeletal proteins.

This conserved site for syndecans starts with the last residue of the transmembrane region and includes the first 10 residues of the cytoplasmic domain. This region, which contains four basic residues, could act as a stop transfer site.
Natriuretic peptide, conserved site (Natr_peptide_CS)
Type: Conserved_site

Atrial natriuretic peptides (ANPs) are vertebrate hormones that play an important role in the control of cardiovascular homeostatis, and sodium and water balance in general . There are different NPs that vary in length but share a common core. All are processed from a single precursor. A disulphide bond resident in the C-terminal section is required for full activity of atriopeptins.

This entry represent a conserved site which includes the two cysteines involved in the disulfide bond, and two conserved glycines that may be important for the conformation of the peptides.
p53 and DNA damage-regulated protein 1 (PDRG1)
Type: Family

p53 and DNA damage-regulated protein 1 (PDRG) mRNA is upregulated by ultraviolet radiation (UV) but downregulated by tumour suppressor p53 . Its expression is increased in multiple human malignancies, suggesting that it could play a role in cancer development and/or progression . It belongs to the prefoldin subunit beta family, whose members are chaperone complex subunits. The function of PDRG is not clear.
Serine/threonine-protein kinase Rio2 (Rio2)
Type: Domain

This entry represents the catalytic domain of protein Rio2 from archaea to human. Rio2 is a conserved serine protein kinase capable of in vitro autophosphorylation, albeit with low activity . In budding yeast, the kinase activity of Rio2 is necessary for the final processing step of maturing the 18S ribosomal rRNA .
DNA (cytosine-5)-methyltransferase 3B, ADD domain (DNMT3B_ADD)
Type: Domain

This entry represents the ADD domain of DNMT3B. The ADD domain is composed of three clearly distinguishable modules that pack together through extensive hydrophobic interactions to form a single globular domain. Packed against this GATA-like finger is a second subdomain, which binds two zinc ions and closely resembles the structure reported for several PHD fingers. Finally, there is a long C-terminal α-helix that runs out from the PHD finger and makes extensive hydrophobic contacts with the N- terminal GATA finger, bringing the N- and C-termini of the ADD domain close together. This combination of fused GATA-like and PHD fingers within a single domain is thus far unique .

In mammals, DNA methylation patterns are thought to be established during embryonic development by de novo DNA methyltransferases 3A and 3B (DNMT3A/3B) . DNMT3A/3B work synergistically to propagate methylation patterns with DNMT3B stimulating DNMT3A activity by promoting its association with nucleosomes . Many DNMT3B isoforms from alternative splicing have been described, among which DNMT3B3 stimulates the basal activity of DNMT3 enzymes, but partially inhibits the stimulatory effect of DNMT3L, whereas DNMT3B4 significantly impairs de novo methylation . DNMT3B is involved in development and is associated with several diseases, including cancers .