SII-SWORD/CoKE huggingface dataset:
Voltage-gated cation channel calcium and sodium (VGCC_Ca_Na)
Type: Family

This entry represents alpha subunits of the voltage-gated sodium channel superfamily.

Voltage-dependent calcium channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular calcium signalling. The opening and closing of these channels by depolarizing stimuli allows calcium ions to enter neurons down a steep electrochemical gradient, producing transient intracellular calcium signals. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus and the known sites of channel regulation by second messengers, drugs, and toxins .

Voltage-dependent sodium channels are transmembrane (TM) proteins are responsible for the depolarising phase of the action potential in most electrically excitable cells . Several structural and functional isoforms are found in mammals, coded for by a multigene family, which leads to different types of sodium ion in excitable tissues.

The structure of sodium channels is based on 4 internal repeats of a 6-helix bundle . The basic structural motif (the 6-helix bundle) is also found in potassium and calcium channel alpha subunits.
Cytochrome b561/Cytochrome b reductase 1-like (CYB561/CYBRD1-like)
Type: Family

This entry represents a group of transmembrane reductases, including CYBRD1/CYB561/CYB561A3 from humans.

Cytochrome b561 is a ferric-chelate reductase that reduces Fe3+ to Fe2+ before its transport from the endosome to the cytoplasm. It probably uses ascorbate as an electron donor .

Cytochrome b reductase 1 (CYBRD1) is an iron-regulated ferric reductase that catalyses the reduction of ferric to ferrous ion in the process of iron absorption in duodenal enterocytes . It shares protein sequence similarity with cytochrome b561, an enzyme involved in the regeneration of ascorbic acid (AA) from semi dehydroascorbic acid (DHA) or ascorbate free radical (AFR) .

CYB561A3 is a lysosomal membrane ascorbate-dependent ferrireductas.
CD44 antigen-like (CD44_antigen-like)
Type: Family

CD44, also known as the hyaluronan receptor , is a polymorphic cell-surface glycoprotein synthesised in a variety of cells. The protein interacts with actin-based cytoskeletons, and co-localises with ERM proteins (ezrin, radixin and moesin) at actin filament- plasma membrane interaction sites. CD44 may be involved in cell migration, adhesion and differentiation in normal cells, as well as in metastasis in cancer cells. It is a receptor for extracellular materials, such as soluble or cell-bound hyaluronic acid, collagen, fibronectin and serglycin. The protein has a single membrane-spanning domain and has a heavily glycosylated extracellular domain; its cytoplasmic domain is reportedly associated with an ankyrin-like protein .

Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. CD44 antigen (Phagocytic glycoprotein I) belongs to the Indian blood group system and is associated with In(a/b) antigen.

In addition to CD44 antigens this entry also includes lymphatic vessel endothelial hyaluronic acid receptor 1, also known as cell surface retention sequence binding protein-1 (CRSBP-1). CRSBP-1, a membrane glycoprotein, can mediate cell-surface retention of secreted growth factors containing CRS motifs such as PDGF-BB. The role of CRSBP-1 is unknown .

This entry appears to be restricted to metazoa.
Secretoglobin family 1C-like (Secretoglobin_1C-like)
Type: Family

Secretoglobins are relatively small, secreted, disulphide-bridged dimeric proteins with encoding genes sharing substantial sequence similarity .

Secretoglobin have a four-helical structure, and in the case of uteroglobin, form homodimers, whereas allergen Fel d 1 forms a tetramer of two heterodimers (chains 1 and 2). The conservation of this primary and quaternary structure indicates that the genome of the eutherian common ancestor of cats, rodents, and primates contained a similar gene pair.

Uteroglobin (blastokinin or Clara cell protein CC10) is a mammalian steroid-inducible secreted protein originally isolated from the uterus of rabbits during early pregnancy . The mucosal epithelia of several organs that communicate with the external environment express uteroglobin. Its tissue-specific expression is regulated by steroid hormones, and is augmented in the uterus by non-steroidal prolactin. Uteroglobin may be a multi-functional protein with anti-inflammatory/immunomodulatory properties, acting to inhibit phospholipase A2 activity , and binding to (and possibly sequestering) several hydrophobic ligands such as progesterone, retinols, polychlorinated biphenyls, phospholipids and prostaglandins . In addition, uteroglobin has anti-chemotactic, anti-allergic, anti-tumourigenic and embryo growth-stimulatory properties. Uteroglobin may have a homeostatic role against oxidative damage, inflammation, autoimmunity and cancer . However, the true biological function of uteroglobin is poorly understood. Uteroglobin consists of a disulphide-linked homodimer with a large hydrophobic pocket located between the two dimers . Each monomer being composed of four helices that do not form a canonical four helix-bundle motif but rather a boomerang-shaped structure in which helices H1, H3, and H4 are able to bind a homodimeric partner . The hydrophobic pocket binds steroids, particularly progesterone, with high specificity. It is a member of the secretoglobin superfamily.

This entry represents the uteroglobin and secretoglobin family 1C (SCGB1C). SCGB1C1 has been shown to be localised to Bowman's glands in the olfactory mucosa . It is thought to act as an odorant-binding protein, with ligands appearing to be small, hydrophobic molecules .
Phosphatidic acid phosphatases-like (PAP-like)
Type: Family

This entry represents a group of membrane-associated phosphatidic acid phosphatases and their homologues mostly found in metazoa, fungi and plants.

In budding yeasts there are two members, Lpp1 and Dpp1. Lpp1 catalyzes the Mg(2+)-independent dephosphorylation of phosphatidate (PA), diacylglycerol pyrophosphate (DGPP), and lysophosphatidate (LPA) . Dpp1, a zinc-regulated enzyme that catalyzes the dephosphorylation of diacylglycerol diphosphate (DGPP) to phosphatidate (PA) and the subsequent dephosphorylation of PA to diacylglycerol (DAG) .

In humans, the members are phospholipid phosphatase 1-5 (PLPP1-5) and phospholipid phosphatase-related protein type 1-5 (PLPR1-5). PLPPs are magnesium-independent phospholipid phosphatase of the plasma membrane that catalyzes the dephosphorylation of a variety of glycerolipid and sphingolipid phosphate esters . PLPR1-5 may not have 2-lysophosphatidate/LPA phosphatase activity due to the lacking of critical residues supporting the reaction mechanism in active phosphatases of this phosphoesterase family.

Plant members of this group are constitutively expressed in many tissues and exhibit both diacylglycerol pyrophosphate phosphatase activity as well as phosphatidate (PA) phosphatase activity . Another lipid phosphate phosphatase (LPP) homologue, Wunen, is a drosophila protein expressed in the central nervous system, which provides repellent activity towards primordial germ cells (PGCs), controls the survival of PGCs and is essential in the migration process of these cells towards the somatic gonadal precursors .
POM121-like protein 1 (POM121-like_prot_1)
Type: Family

Nucleoporin Nup121 or pore membrane protein POM121 is a essential component of the nuclear pore complex (NPC). It has a repeat-containing domain that may be involved in anchoring components of the pore complex to the pore membrane. When overexpressed in cells, POM121 (Nup121) induces the formation of cytoplasmic annulate lamellae (AL) .

This entry includes POM121-like protein 1 and related proteins.
BTBD8, BACK domain (BACK_BTBD8)
Type: Domain

BTBD8 is a BTB-domain-containing Kelch-like protein that may play a role in developmental process. It may also act as a protein-protein adaptor in a transcription complex and thus may be involved in brain development .

This entry represents the BACK domain of BTBD8.
Natural cytotoxicity triggering receptor 3 (NCR3)
Type: Family

NCR3, also known as NKp30, is a natural cytotoxicity receptor expressed on natural killer (NK) cells. It is critically involved in direct cytotoxicity against various tumour cells and directs both maturation and selective killing of dendritic cells . In humans the cell-encoded ligands of NKp30 have been reported, such as heparan sulphates, Galectin-3 , the intracellular protein BCL2-associated athanogene 6 (BAG-6) and the TM cell surface protein B7H6. Several alternative ligands have been reported for NKp30, including pp65 from CMV 11, HA from poxviruses including Vaccinia virus, Duffy binding-ike domain 1alpha from Plasmodium falciparum, and beta-1,3-glucans from the pathogenic fungi Cryptococcus neoformans and Candida albicans .
Small integral membrane protein 29 (SMIM29)
Type: Family

The function of SMIM29 is not clear.
Cysteine-rich and transmembrane domain-containing protein 1-like (CYSTM1-like)
Type: Family

This family includes a group of eukaryotic proteins containing the uncharacterised cysteine-rich, transmembrane (TM) module, CYSTM, found in a wide range of tail-anchored membrane proteins, which may play a role in stress tolerance . This entry includes CYSTM1 from animals, whose function is not clear, the uncharacterised protein YBR016W and YDL012C from yeast.
Proline-rich transmembrane protein 3 (PRRT3)
Type: Family

The function of PRRT3 is not clear.
Small cell adhesion glycoprotein (SMAGP)
Type: Family

SMAGP is a small transmembrane glycoprotein that promotes tumour progression .
Biorientation of chromosomes in cell division protein 1-like 1 (BOD1L1)
Type: Family

This entry represents the human Biorientation of chromosomes in cell division protein 1-like 1 (also known as BOD1L1,

) and related proteins. BOD1L1 is a component of the fork protection machinery required to protect stalled/damaged replication forks from uncontrolled DNA2-dependent resection . It acts by stabilising RAD51 at stalled replication forks and protecting RAD51 nucleofilaments from the antirecombinogenic activities of FBH1 and BLM .

This entry also includes the paralogous BOD1L2 and BOD1 that are required for proper chromosome biorientation through the detection or correction of syntelic attachments in mitotic spindles .
Complement component C8 gamma chain (C8G)
Type: Family

Human C8 is one of five complement components (C5b, C6, C7, C8, and C9) that assemble on bacterial membranes to form a porelike structure referred to as the "membrane attack complex" (MAC) . C8 contains three subunits (C8alpha, C8beta, C8gamma) arranged as a disulfide-linked C8alpha-gamma heterodimer that is noncovalently associated with C8beta .
Sperm-associated microtubule inner protein 5 (SPMIP5)
Type: Family

This entry represents the homologs of Sperm-associated microtubule inner protein 5 (SPMIP5 also known as C10orf82). SPMIP5 is a mammalian sperm-specific microtubule inner protein .
Coiled-coil domain-containing protein 183 (CCDC183)
Type: Family

The function of CCDC183 is not clear.
Cystatin-9-like (CST9-like)
Type: Family

Cystatins (also known as cysteine proteinase inhibitors) are structurally conserved, low molecular weight endogenous cysteine protease inhibitors found in most body compartments and fluids. They play an intra and/or extra-cellular role to inhibit cysteine enzymes (i.e cathepsins), crucial to maintain the protease-inhibitor balance, thus regulating damaging proteolytic activities . It is thought that cystatins may influence the intra- and extracellular catabolism of proteins and peptides, regulate proteolytic processing of prohormones and proenzymes, protect against penetration of normal tissues by malignant cells or microorganisms and modulate local inflammatory processes such as rheumatoid arthritis and purulent bronchiectasis .

Cystatins have been categorised into three classes. Stefins (type I) are unglycosylated proteins of about 100 amino acids lacking disulphide bridges. Type II cystatins are about 120 amino acids and have two intra-chain disulphide bonds. Most of them are found both in tissues and body fluids including saliva. Kininogens (type III) are single chain glycoproteins containing three cystatin-like domains .

Cystatin 9 (CST9) is a small ~18kDa human protein member of the type 2 cystatin superfamily . It may play a role in hematopoietic differentiation or inflammation. It may be targeted through the Golgi via the secretory pathway . It has been shown to have immunomodulatory and antibacterial effects against Francisella tularensis infection of the lung .

This entry represents cystatin 9 and cystatin 9-like proteins.
Neuromedin S (NmS)
Type: Family

Neuromedin S (NmS) is a neuromedin U-related peptide. It has shown to possess anorexigenic and circadian rhythm-modulating properties in mammals. NmS expression is localised predominantly in the core region of the suprachiasmatic nucleus within the hypothalamus, but also in spleen and testis . Other biological functions include antidiuretic action via release of vasopressin, milk ejection via release of oxytocin and regulation of the circulatory system, immune reactions and insulin secretion. NmU (neuromedin U) and NmS are involved in thermoregulation via the sympathetic nervous system (beta3 adrenergic receptors) and prostaglandin E2 .
Heat shock protein beta-8 (HSPB8)
Type: Family

HSPB8, also known as HSP22, is a small heat shock protein that interacts with itself, cvHSP (HSPB7), MKBP (HSPB2), HSP27 alphaB-crystallin and HSP20 .
Urotensin-2B (U-IIB)
Type: Family

Urotensin II has been reported as the most potent known vasoconstrictor, involved in the cardiovascular regulation and osmoregulation . Urotensin II-related proteins mRNA are specifically expressed in several cerebral structures and tissues (heart, seminal vesicle), suggesting a role in the regulation of autonomic, cardiovascular and reproductive functions .

This entry includes Urotensin-2B (U-IIB) proteins. U-IIB inhibits glucagon-like peptide-1(GLP-1) secretion in mouse intestinal crypts and organoid through the activation of the somatostatin receptor 5 (SSTR5) .
Polyferredoxin MvhB-like (MvhB-like)
Type: Family

This entry includes a group of polyferredoxins, including MvhB from Methanobacterium thermoautotrophicum and Methanocaldococcus jannaschii FwdF. MvhB is encoded by mvhB of the mvhDGAB operon and is predicted to contain 12 [4Fe-4S] clusters, and was therefore suggested to be a polyferredoxin .
Ring-hydroxylating dioxygenase large subunit NdoB-related protein, N-terminal Rieske domain (Rieske_N)
Type: Domain

This entry represents the Rieske domain found at the N-terminal of some uncharacterised proteins from bacteria. Proteins containing this domain also contain a C-terminal domain found in the NDO-like alpha subunit of the ring-hydroxylating dioxygenase. However, the characterised naphthalene 1,2-dioxygenase large subunit NdoB from Pseudomonas sp. is not included in this entry.
Ring-hydroxylating dioxygenase, large/alpha subunit AhdA1c-like, C-terminal (AhdA1c-like_alpha_C)
Type: Domain

This entry represents the C-terminal domain of the large/alpha subunit (ahdA1c) of a ring-hydroxylating dioxygenase from Sphingomonas sp. strain P2 and related Rieske-type non-heme iron aromatic ring-hydroxylating oxygenases.

In Sphingomonas sp. strain P2, AhdA3A4A2cA1c is one of three known isofunctional salicylate 1-hydroxylase complexes, involved in phenanthrene degradation, which catalyze the monooxygenation of salicylate, the metabolite of phenanthene degradation, to produce catechol. This complex prefers salicylate over other substituted salicylates; the other two salicylate 1-hydroxylases have different substrate preferences .

The ring-hydroxylating oxygenase components are oligomers, either (alpha)n or (alpha)n(beta)n. The alpha subunits are the catalytic components and have an N-terminal domain, which binds a Rieske-like 2Fe-2S cluster, and a C-terminal domain which binds the non-heme Fe2. The Fe2 is co-ordinated by conserved His and Asp residues. This entry also includes TPDA1/TPDA2 from Comamonas sp. , NAGG from Ralstonia sp. , and ANDAC from Burkholderia cepacia .
POU class 2 homeobox associating factor 3 (OCAT2)
Type: Family

POU class 2 homeobox associating factor 3 (protein OCAT2, also known as colorectal cancer-associated protein 2 (COLCA2)) is expressed in cytoplasm of many cell types of epithelial (normal and tumoral), lymphoid, myeloid, mesenchymal and other origins and has orthologs in multiple mammals. It is a transcriptional coactivator that specifically associates with POU2F3 and forms a complex that drives the development of tuft cells, a rare a rare chemosensory cells that coordinate immune and neural functions within mucosal epithelial tissues . It has been suggested to have critical functions in suppressing tumor formation in epithelial cells. High levels of OCAT2 in immune and other cells of the micro-environment may also provide protection against cancer cell growth .
Ring-hydroxylating dioxygenase, alpha subunit NdoB-like, C-terminal (RHO_NdoB-like_C)
Type: Domain

This entry represents the C-terminal domain of the large subunit (NdoB) of naphthalene 1,2-dioxygenase (NDO) and related aromatic ring hydroxylating dioxygenases .

The ring-hydroxylating oxygenase components are oligomers, either (alpha)n or (alpha)n(beta)n. The alpha subunits are the catalytic components and have an N-terminal domain, which binds a Rieske-like 2Fe-2S cluster, and a C-terminal domain which binds the non-heme Fe2. The Fe2 is co-ordinated by conserved His and Asp residues. This entry also includes BphA1 from Rhodococcus jostii , DntAc from Burkholderia sp. , and HcaE from Escherichia coli .
Protein unc-93 homolog B1 (UNC93B1)
Type: Family

UNC93B1 is a multi-transmembrane domain-containing protein that plays an essential role in signalling by the nucleotide-sensing Toll-like receptors (TLRs), including TLR3, TLR7 and TLR9 . UNC93B1 delivers the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes . It has been shown to recruit Syntenin-1 and dampen TLR7 signalling and prevent autoimmunity . It also binds TLR9, and the release of TLR9 from UNC93B1 is required for TLR9 to function . Mutations in the UNC93B1 gene that result in aberrant TLR trafficking can lead to autoimmune disease .
Lateral signaling target protein 2, FYVE domain (FYVE_LST2)
Type: Domain

Lateral signaling target protein 2 (Lst2) is a monoubiquitinylated phosphoprotein that functions as a negative regulator of epidermal growth factor receptor (EGFR) signaling. Unlike other FYVE domain-containing proteins, Lst2 displays primarily non-endosomal localization. Its endosomal localization is regulated by monoubiquitinylation. Lst2 physically binds Trim3, also known as BERP or RNF22, which is a coordinator of endosomal trafficking and interacts with Hrs and a complex that biases cargo recycling .

This entry represents the FYVE domain of Lst2.
RNF4, RING finger, HC subclass (RING-HC_RNF4)
Type: Domain

RNF4 is a SUMO-targeted E3 ubiquitin-protein ligase with a pivotal function in the DNA damage response (DDR) through interacting with the deubiquitinating enzyme ubiquitin-specific protease 11 (USP11), a known DDR-component, and further facilitating DNA repair . It plays a novel role in preventing the loss of intact chromosomes and ensures the maintenance of chromosome integrity. Moreover, RNF4 is responsible for the UbcH5A-catalyzed formation of K48 chains that target SUMO-modified promyelocytic leukemia (PML) protein for proteasomal degradation in response to arsenic treatment . It also interacts with telomeric repeat binding factor 2 (TRF2) in a small ubiquitin-like modifiers (SUMO)-dependent manner and preferentially targets SUMO-conjugated TRF2 for ubiquitination through SUMO-interacting motifs (SIMs) . Furthermore, RNF4 can form a complex with a Ubc13-ubiquitin conjugate and Ube2V2. It catalyzes K63-linked polyubiquitination by the Ube2V2-Ubc13 (ubiquitin-loaded) complex . Meanwhile, RNF4 negatively regulates nuclear factor kappa B (NF-kappaB) signaling by down-regulating transforming growth factor beta (TGF-beta)-activated kinase 1 (TAK1)-TAK1-binding protein2 (TAB2) .

This entry represents the C3HC4-type RING-HC finger.
Protein LRATD1/ LRATD2 (LRATD1_LRATD2)
Type: Family

This entry includes protein LRATD1 (also known as FAM84A) and LRATD2. LRATD1 has been linked to cancer progression
. LRATD2 is expressed in esophageal squamous cell carcinomas .
E3 ubiquitin ligase BIG BROTHER-like (AtBBR-like)
Type: Family

This entry represents a group of plant proteins, including AtBBR (At3g19910) from Arabidopsis. Their function is not clear. They share protein sequence similarity with E3 ubiquitin-protein ligase BIG BROTHER in their RING finger domain .
Leucine-rich melanocyte differentiation-associated protein (LRMDA)
Type: Family

LRMDA is required for melanocyte differentiation. Mutations in the LRMDA gene cause autosomal-recessive albinism in humans
.
C-type lectin domain family 9 member A (CLEC9A)
Type: Family

CLEC9A is a membrane protein with a single extracellular C-type lectin domain . It is expressed on the surface of the mouse and human dendritic cell subsets specialized for the uptake and processing of material from dead cells. It has been shown to bind filamentous form of actin and associates with actin-binding domains of cytoskeletal proteins .
Cysteine and histidine-rich domain-containing protein RAR1 (RAR1)
Type: Family

This entry represents a group of CHORD domain-containing proteins from plants, including RAR1 (At5g51700) from Arabidiopsis. RAR1 has two CHORD domains. RAR1 is required for several R gene-mediated resistance responses in monocotyledonous and dicotyledonous plant species against different pathogen classes .
Ubiquitin-like protein 4B (UBL4B)
Type: Family

The function of UBL4B is not clear.
Killer cell lectin-like receptor subfamily G member 2 (KLRG2)
Type: Family

The function of KLRG2 is not clear.
ASH1-like, PHD finger (PHD_ASH1L)
Type: Domain

This entry includes ASH1 from flies and ASH1L from mammals. ASH1/ASH1L are the members of the Trithorax family.

In Drosophila melanogaster, ASH1 (absent, small, or homeotic 1) is an epigenetic transcriptional regulator of HOX genes. Drosophila ASH1 has been shown to methylate specific lysines in histones H3 and H4. Mammalian ASH1 has been shown to methylate histone H3 .

ASH1L methylates Lys36 of histone H3 independently of transcriptional elongation to promote the establishment of Hox gene expression by counteracting Polycomb silencing . It can suppress interleukin-6 (IL-6), and tumour necrosis factor (TNF) production in Toll-like receptor (TLR)-triggered macrophages, and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20 . ASH1L contains an associated with SET domain (AWS), a SET domain, a post-SET domain, a bromodomain, a bromo-adjacent homology domain (BAH), and a plant homeodomain (PHD) finger .

This entry represents the PHD domain of ASH1 and ASH1L.