SII-SWORD/CoKE huggingface dataset:
Two pore channel protein 1 (TPC1_animal)
Type: Family

Two-pore segment channels (TPCs or TPCNs) are located in membranes of acidic intracellular organelles (such as endo-lysosomes and plant vacuoles) and contain two putative pore-forming repeats. Each of these repeats contains six transmembrane segments and an intervening pore-loop, an architecture featured in voltage-gated channels . Functional TPC channels are assembled from two TPC protein subunits forming a pore that conducts mainly Ca2 and Na. TPCs exist as three isoforms (TPC1-3): TPC1 and TPC2 are the most universal isoforms since TPC3 is absent from the genomes of many animals including those of human, mice, rats and flies .

This entry represents TPC1 from animals . TPC1 was first identified as an NAADP (nicotinic acid adenine dinucleotide phosphate)-regulated Ca2+ channel. Later it was shown to serve as a voltage-gated highly-selective Na+ channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) that senses pH changes and confers electrical excitability to organelles .
Caprin (Caprin)
Type: Family

Caprins (cytoplasmic activation/proliferation-associated protein) may regulate the transport and translation of mRNAs of proteins involved in synaptic plasticity in neurons and cell proliferation and migration in multiple cell types . In humans, there are two caprins, caprin1 and caprin2. Caprin1 (also known as Rng105) may regulate the transport and translation of mRNAs of proteins involved in synaptic plasticity in neurons and cell proliferation and migration in multiple cell types . Caprin2 is expressed in the developing vertebrate lens .
Nuclear receptor coactivator 1, basic helix-loop-helix (NCOA1_bHLH)
Type: Domain

This entry represents the N-terminal basic helix-loop-helix (bHLH) domain of NCOA1.

Nuclear receptor coactivator 1 (NCOA1, also known as SRC-1) belongs to the SRC/p160 nuclear receptor coactivator family, which contains proteins that are ligand-dependent transcription factors . These receptors can function as molecular switches .

NCOA1 directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion . It is involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs) . It is also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors . It plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors . It can be regulated by sumoylation and ubiquitination .
Nuclear receptor coactivator 2, basic helix-loop-helix (NCOA2_bHLH)
Type: Domain

Nuclear receptor coactivator 2 (NCOA2, also known as Tif2) belongs to the SRC/p160 nuclear receptor coactivator family, which contains proteins that are ligand-dependent transcription factors . These receptors can function as molecular switches .

NCOA2 is a transcriptional coactivator for steroid receptors and nuclear receptors. It functions as a coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1) . Together with NCOA1, it is required to control energy balance between white and brown adipose tissues .

This entry represents the N-terminal basic helix-loop-helix (bHLH) domain of NCOA2.
Sodium leak channel NALCN (NALCN)
Type: Family

Sodium leak channel non-selective protein (NALCN) was first described as a voltage-independent, cation-nonselective channel which is permeable to sodium, potassium and calcium ions , however, it was recently reported to be selective only for monovalent cations and to be blocked by extracellular divalent cations . Coexpression of NALCN, UNC79, UNC80, and NALF1 results in voltage-dependent NALCN currents . It is responsible for the background sodium ion leak current in neurons and controls neuronal excitability. It is activated either by neuropeptides substance P or neurotensin . NALCN is required for normal respiratory rhythm and neonatal survival .
Afadin (Afadin)
Type: Family

Afadin (also known as MLLT4 or AF-6) is an actin filament (F-actin) and Rap1 small G protein-binding protein that plays a role in cell adhesion, cell polarisation, migration, survival, proliferation, and differentiation . It binds to nectins and regulates actomyosin. organisation in the formation of cell-cell junctions . It controls the levels of RhoA activation, which may critically regulate the lymphangiogenesis of mouse embryos . It is also involved in oncogenesis and metastasis .
Recoverin family (Recoverin)
Type: Family

A number of other proteins including visinin, hippocalcin, neurocalcin,
S-modulin, visinin-like protein, frequenin, guanylyl cyclase-activating proteins GCAP-1 and GCAP-2 belong to this family. All of the family members are generally N-myristoylated proteins containing four EF-hand calcium-binding consensus motifs.

Recoverin is a Ca(2+) -binding protein that controls phosphorylation of the visual receptor rhodopsin by inhibiting rhodopsin kinase (GRK-1) in photoreceptor cells . It serves as a cancer-retina antigen that is expressed in retina and tumour cells and evokes antibodies and/or T cells in patients with cancer .
Centromere protein W (CENP-W)
Type: Family

Centromere protein W (CENP-W) is a component of the CENPA-NAC (nucleosome-associated) complex, which plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation . CENP-W gene is up-regulated in various types of cancers and was first identified as a putative oncogene, CUG2 . It can be regulated by CSN5, a component of the CSN complex involved in protein degradation via the ubiquitin-proteasome pathway . The DNA-binding regions in CENP-T or CENP-W is essential for inducing positive supercoils into DNA and for the kinetochore targeting of the CENP-T-W-S-X complex .
Mucin-16 (MUC16)
Type: Family

Mucin-16 (also known as CA125) belongs to the mucin family. They are high molecular weight proteins that are components of mucus and are synthesised and secreted by specialised cells of the epithelium (goblet cells, cells of mucous glands) or non mucin-secreting cells .

Mucin-16 is over-expressed in human epithelial tumors including ovarian, breast and digestive tract carcinomas . Its expression is an independent predictor of poor outcome in pancreatic ductal adenocarcinomas and probably in esophageal adenocarcinomas and gastric adenocarcinomas, being proposed to be used as a prognostic marker and a therapeutic target . It interacts with Src family kinases (SFKs) and this may affect cell-cell adhesion of epithelial cancer cells .
Periphilin-1 (Pphln1)
Type: Family

This entry represents Periphilin-1 (Pphln1) in vertebrates.

Periphilin-1 is a component of the HUSH complex, a multiprotein complex that mediates epigenetic repression. The HUSH complex is recruited to genomic loci rich in H3K9me3 and is probably required to maintain transcriptional silencing . This protein acts as a transcriptional corepressor and regulates the cell cycle, probably via the HUSH complex . It is involved in epithelial differentiation and contributes to epidermal integrity and barrier formation . It is associated with gastric cancer .
ARID4B, ARID/BRIGHT domain (ARID4B_ARID/BRIGHT)
Type: Domain

This entry represents the AT-rich ARID/BRIGHT DNA binding domain of ARID4B.

AT-rich interactive domain-containing protein 4B (ARID4B, also known as RBBP1-like 1 (RBBP1L1)) is homologous to ARID4A (or Retinoblastoma-binding protein 1 (RBBP1)) which are involved in cell cycle control . Together with retinoblastoma protein (RB) and Sin3 they form the Sin3 complex involved in gene regulation and epigenetic regulation functions . They also function as transcriptional coactivators for the androgen receptor (AR) and RB, being important for the AR and RB regulatory pathways, involved in the regulation of Sertoli cell function and male fertility . These proteins share the same domain architecture consisting of an interdigitated double Tudor, PWWP, ARID, chromo barrel and R2 domains, connected by intrinsically disordered regions.
Blue (type 1) copper protein, binding site (BlueCu_1_BS)
Type: Binding_site

Blue (type 1) copper proteins constitute a diverse class of proteins, including small blue proteins and multicopper oxidases. They bind copper and are characterised by an intense electronic absorption band near 600 nm .

The most well known members of this class of proteins are the small blue proteins, which includes azurins and plastocyanins. It is a group of monomeric proteins which contain one copper ion per molecule. The plant chloroplastic plastocyanins exchange electrons with cytochrome c6, and the distantly related bacterial azurins exchange electrons with cytochrome c551. This group also includes amicyanin from bacteria such as Methylobacterium extorquens or Paracoccus versutus (Thiobacillus versutus) that can grow on methylamine; auracyanins A and B from Chloroflexus aurantiacus ; blue copper protein from Alcaligenes faecalis; cupredoxin (CPC) from Cucumis sativus (Cucumber) peelings ; cusacyanin (basic blue protein; plantacyanin, CBP) from cucumber; halocyanin from Natronomonas pharaonis (Natronobacterium pharaonis) , a membrane associated copper-binding protein; pseudoazurin from Pseudomonas; rusticyanin from Thiobacillus ferrooxidans ; stellacyanin from Rhus vernicifera (Japanese lacquer tree); umecyanin from the roots of Armoracia rusticana (Horseradish); and allergen Ra3 from ragweed. This pollen protein is evolutionary related to the above proteins, but seems to have lost the ability to bind copper.

Although there is an appreciable amount of divergence in the sequences of all these proteins, the copper ligand sites are conserved. This entry represents a conserved site that includes two of the ligands: a cysteine and a histidine.
Large ribosomal subunit protein eL20 (Ribosomal_eL20)
Type: Family

This entry represents the large ribosomal subunit protein eL20 from archaea (previously known as 50S ribosomal protein L18A) and eukaryotes (also known as L20 and 60S ribosomal protein L18a).

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 .
Ribonuclease E (RNase_E)
Type: Family

Ribonuclease E (RNase E) is an endoribonuclease that plays a central role in RNA processing and decay. It is required for the maturation of 5S and 16S rRNAs, and the majority of tRNAs. It is also involved in the degradation of most mRNAs . It is a major subunit of the eubacterial degradosome - a large multiprotein complex involved in RNA processing and degradation in E. coli and other proteobacteria . It is required to initiate rRNA degradation during both starvation and quality control; acts after RNase PH (rph) exonucleolytically digests the 3'-end of the 16S rRNA . Degradation of 16S rRNA leads to 23S rRNA degradation. RNase E is a multidomain protein containing an amino-terminal catalytic domain, a central RNA-binding domain, and carboxy-terminal binding sites for the other major components of the RNA degradosome .
NADPH-dependent diflavin oxidoreductase 1 (NDOR1)
Type: Family

NDOR1, also known as Tah18 in budding yeast, is a conserved NAPDH-dependent diflavin reductase from eukaryotes. It is a component of the cytosolic iron-sulfur (Fe-S) protein assembly (CIA) machinery and part of an electron transfer chain functioning in an early step of cytosolic Fe/S biogenesis. It transfers electrons from NADPH to the Fe/S cluster DRE2 in budding yeasts or CIAPIN1 in humans .
ATP-dependent DNA helicase Rrm3 (Rrm3)
Type: Family

This entry represents ATP-dependent DNA helicase Rrm3 from budding yeasts. It is a 5' to 3' DNA replicative helicase recruited to paused replisomes to promote fork progression throughout nonhistone protein-DNA complexes, naturally occurring impediments that are encountered in each S phase where replication forks pauses . It shares protein sequence similarities with another DNA helicase, Pif1. However, their functions are different. Rrm3 promotes telomere replication, while Pif1 inhibits telomere replication . They also have opposite effects on replication fork progression in ribosomal DNA .
PAN2, UCH domain (PAN2_UCH_dom)
Type: Domain

The poly(A)-specific nuclease (PAN) is a deadenylating enzyme involved in cytoplasmic mRNA turnover and consists of two subunits, PAN2 and PAN3, which form a conserved complex acting in the initial trimming of poly(A) tails, a process followed by the processive action of CCR4-NOT complex. PAN2 is the catalytic subunit and has two independent structural units, the N-terminal assembly unit which engages in a bipartite interaction with PAN3 dimers and the C-terminal catalytic unit . The C-terminal unit contains the ubiquitin C-terminal hydrolase (UCH) domain, represented in this entry, and a RNase domain of the DEDD superfamily (

) .
Succinate dehydrogenase assembly factor 2, mitochondrial (SDHAF2)
Type: Family

Succinate dehydrogenase assembly factor 2 (SDHAF2, also known as Sdh5 or Emi5) is required for insertion of FAD cofactor into SDH1, the catalytic subunit of succinate dehydrogenase (SDH) . SDH complex is a component of both the electron transport chain and the tricarboxylic acid cycle.

This entry includes mitochondrial SDHAF2 from fungi and metazoans. In humans, mutations in SDHAF2 gene cause paragangliomas 2 (PGL2), which is a neural crest tumor usually derived from the chromoreceptor tissue of a paraganglion .
tRNA-specific adenosine deaminase (tRNA_aden_deaminase)
Type: Family

tRNA-specific adenosine deaminase catalyses the deamination of adenosine to inosine at the wobble position 34 of tRNA(Arg2) .
tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit (Trm82)
Type: Family

This entry represents tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit Trm82 and its homologues, wuho from flies and WDR4 from humans.

In Saccharomyces cerevisiae, Trm82 is the non-catalytic subunit of the tRNA methyltransferase complex which consists of Trm8 and Trm82 . It is essential for the enzyme activity and may function in regulating the the Trm8 protein .

In humans, WDR4 forms the tRNA methyltransferase complex with METTL1 (Trm8 homologue). It is required to stabilise and induce conformational changes of the catalytic subunit METTL1 . It is required for the formation of N7-methylguanine at position 46 (m7G46) in tRNA and also for the formation of N7-methylguanine at internal sites in a subset of mRNAs . WDR4 is also involved in the methylation of a specific subset of miRNAs, such as let-7 . Independently of METTL1, it also plays a role in genome stability: localizes at the DNA replication site and regulates endonucleolytic activities of FEN1 .
Adenylyltransferase and sulfurtransferase MOCS3/Uba4 (MOCS3/Uba4)
Type: Family

This entry includes adenylyltransferase and sulfurtransferase MOCS3 and its homologue, Uba4, from yeasts.

In budding yeasts, Uba4 receives sulphur from Nfs1 and Tum1 . Uba4 then forms an acyl adenylate intermediate with the C-terminal of the Urm1 protein, and then forms an acyl disulfide bond between Uba4 Cys397 and the Urm1 C-terminal glycin . Subsequently, the activated Urm1 acts as a sulphur carrier in the process of eukaryotic transfer RNA (tRNA) thiolation .

MOCS3 plays a central role in 2-thiolation of mcm5S2U at tRNA wobble positions of cytosolic tRNA(Lys), tRNA(Glu) and tRNA(Gln) . It is also essential during biosynthesis of the molybdenum cofactor . MOCS3 acts by mediating the C-terminal thiocarboxylation of sulfur carriers Urm1 and MOCS2A (the small subunit of molybdopterin synthase) .
Molybdenum cofactor sulfurase (MoCo_sulfurase)
Type: Family

Molybdenum cofactor sulfurase sulfurates the molybdenum cofactor (MoCo). Sulfation of molybdenum is essential for xanthine dehydrogenase (XDH) and aldehyde oxidase (ADO) enzymes in which molybdenum cofactor is liganded by one oxygen and one sulfur atom in active form . This entry also includes its plant homologue, LOS5/ABA3. In plants, the sulfurylated MoCo is a cofactor of ABA-aldehyde oxidase that functions in the last step of ABA biosynthesis .
Molybdopterin synthase sulfur carrier subunit, eukaryote (MOCS2A_euk)
Type: Family

MOCS2A is a the small subunit of the molybdopterin synthase complex that catalyses the conversion of precursor Z into molybdopterin by mediating the incorporation of 2 sulfur atoms into precursor Z to generate a dithiolene group. In the complex, MOCS2A serves as sulfur donor by being thiocarboxylated at its C terminus by UBA4 . After interaction with MOCS2B, the sulfur is then transferred to precursor Z to form molybdopterin .

This entry represents the Molybdopterin synthase sulfur carrier subunit from eukaryotes.
Molybdopterin synthase catalytic subunit, eukaryotes (MOCS2B_euk)
Type: Family

Eukaryotic molybdopterin synthase, like the Escherichia coli MoaD-MoaE counterpart, is a heterotetramer that is composed of two subunits: MOCS2A and MOCS2B. MOCS2B is the catalytic subunit of the molybdopterin synthase complex (MOCS2), a complex that catalyses the conversion of precursor Z into molybdopterin. MOC2SB acts by mediating the incorporation of two sulfur atoms from thiocarboxylated MOCS2A (the small MOCS2 subunit which functions as a sulfur carrier) into precursor Z to generate a dithiolene group .

Mutations in human MOCS2B gene cause Molybdenum cofactor deficiency type B (MOCOD type B), an autosomal recessive disease which leads to the pleiotropic loss of all molybdoenzyme activities and is characterised by severe neurological damage, neonatal seizures and early childhood death .
Ubiquitin specific protease UPS, catalytic domain (USP)
Type: Domain

This entry represents the entire USP domain.
The USP catalytic core can be divided into six conserved boxes that are present in all USP domains. Box 1 contains the catalytic Cys residue, box 5 contains the catalytic His

, and box 6 contains the catalytic Asp/Asn residue. All boxes show several additional conserved features and residues. Boxes 3 and 4 contain a Cys-X-X-Cys motif each, which have been shown to constitute a functional zinc-binding motif. Potentially, zinc-binding facilitates folding of the USP core, helping the interaction of sequence motifs some few hundred residues apart. USP domains share a common conserved fold. The USP domain resembles an open hand containing Thumb, Palm and Fingers subdomains. The catalytic triad resides between the Thumb (Cys) and Palm subdomains (His/Asp) .

Protein ubiquitination is a reversible posttranslational modification, which affects a large number of cellular processes including protein degradation, trafficking, cell signaling and the DNA damage response. Ubiquitination is reversible, and dedicated deubiquitinases exist which hydrolyze isopeptide bonds. Ubiquitin specific proteases (USPs) (

) are the largest family of deubiquitinating enzymes. USP domains consist of a common conserved catalytic core which is interspersed at five points with insertions, some of which as large as the catalytic domain itself. The insertions can fold into independent domains that can be involved in the regulation of deubiquitinase activity. As commonly found in signaling proteins, many USP deubiquitinases have a modular architecture, and not only contain a catalytic domain but also additional protein-protein interaction and localisation domains. Most USP domains cleave the isopeptide linkage between two ubiquitin molecules, and hence contain (at least) two ubiquitin-binding sites, one for the distal ubiquitin, the C terminus of which is linked to the Lys residue on the proximal ubiquitin in a second, proximal binding site . The USP domain forms the peptidase family C19 .
Ubiquitin-specific peptidase-like, SUMO isopeptidase (Peptidase_C98)
Type: Domain

Peptidase C98 is a small family of SUMO - small ubiquitin-related modifier - isopeptidases found in eukaryotes. Reversible attachment of SUMO is an essential protein modification in all eukaryotic cells. SUMO-specific isopeptidase USPL1 neither binds nor cleaves ubiquitin, but is a potent SUMO isopeptidase. The invariant residues required for SUMO binding and cleavage, in

are Cys-236, His-456 and Asp-472, all of which are fully conserved in the family. Member proteins are low-abundance proteins that colocalise with coilin in Cajal bodies. Peptidase C98 depletion does not affect global sumoylation, but causes striking coilin mis-localisation and impairs cell proliferation, functions that are not dependent on the catalytic activity. Thus, Peptidase C98 represents a third type of SUMO protease, with essential functions in Cajal body biology .

This entry represents the catalytic domain.
Adenine deaminase type 2 (ADE)
Type: Family

Adenine deaminase (

) hydrolyses adenine to form hypoxanthine and ammonia. The enzyme is part of a large metal dependent hydrolase superfamily . It plays an important role in the purine salvage pathway and in nitrogen catabolism.

This entry represents the type 2 adenine deaminase that is more related to the bacterial and eukaryotic adenosine deaminases than to Bacillus subtilis adenine deaminase and its bacterial homologues .
Adenosine deaminase (A_deaminase)
Type: Family

Adenosine deaminases (

) are involved in purine metabolism. They are required for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues. Adenosine deaminases convert adenosine to the related nucleoside inosine by the substitution of the amino group for a hydroxyl group. These enzymes are distantly related to AMP deaminases .
Reductive dehalogenase domain (RDH_dom)
Type: Domain

This domain is most frequently associated with a Fer4 iron-sulfur cluster towards the C-terminal region. It is found in reductive dehalogenases and 4Fe-4S dicluster domain proteins , such as Trichloroethene reductive dehalogenase and Chloroethene reductive dehalogenase .