SII-SWORD/CoKE huggingface dataset:
Inducible T-cell costimulator (ICOS)
Type: Family

ICOS is an inducible T-cell co-stimulator with homology to CD28 . CD28 and ICOS function similarly during expansion, survival and differentiation of T cells. They are necessary for proper IgG responses. However, CD28 induces IL-2 production, while ICOS is more potent in the induction of IL-10 production .
VSIG4, immunoglobulin variable (IgV)-like domain (VSIG4_IgV)
Type: Domain

The N-terminal domain of V-set and Ig domain-containing 4 (VSIG4), also referred to as CRIg or Z39Ig, belongs to the IgV family of immunoglobulin-like domains . A predominant feature of most Ig domains is a disulfide bridge connecting the two β-sheets with a tryptophan residue packed against the disulfide bond .

V-set and Ig domain-containing 4 (VSIG4) is a strong negative regulator of T cell proliferation and IL-2 production . It also negatively regulates macrophage activation by activating the PI3K/Akt-STAT3 pathway, leading to pyruvate dehydrogenase kinase-2 (PDK2) upregulation and subsequent phosphorylation of pyruvate dehydrogenase, which results in reduction in pyruvate/acetyl-CoA conversion, reduction in mitochondrial reactive oxygen species secretion, and macrophage inhibition .
Lymphocyte antigen 86 (LY86)
Type: Family

Lymphocyte antigen 86 (LY86, also known as MD-1) is a secretory glycoprotein that regulates subsequent T cell activation and cytokine production .
Zinc finger protein 839 (ZN839)
Type: Family

The function of zinc finger protein 839 is not known.
Nuclear receptor coactivator 4 (NCoA-4)
Type: Family

Nuclear receptor coactivator 4, also known as ARA70, is a coactivator for the androgen receptor (AR) and can function as a ligand-enhanced coactivator of PPARgamma. AR can suppress PPARgamma-ARA70 transactivation, suggesting cross-talk between PPARgamma- and AR-mediated responses in adipocytes . NCOA4 has been identified as a selective cargo receptor for the autophagic turnover of ferritinin, a critical process for regulation of iron homeostasis . This entry also includes Nuclear receptor coactivator 4-B from Xenopus laevis which inhibits activation of DNA replication origins, possibly by obstructing DNA unwinding via interaction with the MCM2-7 complex. This protein binds chromatin before initiation of DNA replication and detaches during replication .
Elongin-C (ELC1)
Type: Family

Elongin-C is a highly conserved protein found in a variety of multiprotein complexes in human, rat, fly, worm, and yeast cells . Budding yeast elongin-C homologue, Elc1, forms a complex with Cul3 that is required for Pol II polyubiquitylation and degradation . Elc1 also plays a role in global genomic repair . In humans, elongin-C works as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL) .
N-alpha-acetyltransferase 40 (NAA40)
Type: Family

NAA40 is an N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A . It has a very specific selectivity for histones H4 and H2A N-termini and specifically recognizes the 'Ser-Gly-Arg-Gly sequence' . It is conserved from yeast to human. Its budding yeast homologue is known as Nat4 .
Transmembrane protein TMEM114/TMEM235 (TMEM114/TMEM235)
Type: Family

The functions of the closely related transmembrane proteins TMEM114 and TMEM235 are not known. TMEM114 has a role in eye development .
G-protein coupled receptor Aex-2 (Aex-2)
Type: Family

Aex-2 is a G-protein-coupled receptor on the GABAergic neurons in nematodes and is the receptor for the Nlp-40 neuropeptide. In this way Nlp-40 delivers temporal information to downstream neurons to execute rhythmic behaviours .
Protein of unknown function DUF5527 (DUF5527)
Type: Family

This family of uncharacterised proteins is found in vertebrates.
Signal peptidase complex-like protein DTM1 (DTM1)
Type: Family

DTM1 is an endoplasmic reticulum (ER) membrane protein present in cereals. It is thought to play important roles in the ER membrane during early tapetum development and also in meiocyte development .
RING1 and YY1-binding protein/YY1-associated factor 2 (RYBP/YAF2)
Type: Family

Proteins included in this entry have an N-terminal RanBP2-type zinc finger and a Yaf2/RYBP C-terminal binding motif. Proteins with these regions include Yaf2 and RYBP proteins, which are homologous parts of the PRC1 complex .

RYBP is a zinc finger protein with an essential role during embryonic development, which binds transcriptional factors, Polycomb products, and mediators of apoptosisis . RYBP also binds ubiquitin and Cbx proteins via the C-terminal docking module . RYBP is natively unstructured until it binds to the C-terminal region of the Polycomb protein Ring1B or to DNA . Yaf2 binds to MYC and inhibits MYC-mediated transactivation .
Fimbrin/Plastin (Fimbrin/Plastin)
Type: Family

This entry includes fimbrin and plastin from yeasts to humans. They are actin filament-binding proteins that cross-linking actin filaments into tight bundles .

Mammlian fimbrin, also known as plastin, has three isoforms: T-plastin (Plastin-3) is expressed in cells from solid tissue, whereas L-plastin (Plastin-2) occurs predominantly in hematopoietic cells. The third isoform, I-plastin (Plastin-1), is specifically expressed in the small intestine, colon and kidney .
Mitochondrial adapter protein MCP1 (MCP1)
Type: Family

Mcp1 is a mitochondrial protein involved in mitochondrial lipid homeostasis in yeast. It is a Vps13 adaptor protein, promoting vacuole-mitochondria contacts .
NADH-ubiquinone oxidoreductase 9.5kDa subunit (Nuo9.5)
Type: Family

This 9.5kDa ubiquinone-binding protein (Nuo9.5) from yeast is an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) . It plays an important role in creating the electrochemical gradient that powers mitochondrial adenosine triphosphate synthesis. Nuo9.5 is a single-pass membrane protein and a fungal subunit homologous to NADH dehydrogenase 1 alpha subcomplex subunit 3 (NDUFA3) that is considered an accessory subunit.
Uncharacterized protein ZC21.8 (ZC21.8)
Type: Family

The function of this family of proteins from Caenorhabditis is not known.
Uncharacterized 22kDa protein in aldolase locus (Unchar_22kDa)
Type: Family

The function of this family of proteins is not known. They are found in flagellated protists, such as Trypanosoma and Leishmania.
Uncharacterized protein KIAA0040-like (KIAA0040-like)
Type: Family

The function of this family of proteins is not known. It includes human KIAA0040, which has been linked to alcohol dependence .
Uncharacterized protein C3H7.08c (C3H7.08c)
Type: Family

The function of this family of fungal proteins is not known.
Uncharacterized protein C553.12c (C553.12c)
Type: Family

The function of this family of fungal proteins is not known.
Uncharacterized protein MJ1020-like (MJ1020-like)
Type: Family

This family of prokaryotic proteins has not been characterised.
Bacterial ceramide synthase-like (BcerS-like)
Type: Family

This family includes the bacterial ceramide synthase BcerS from Caulobacter crescentus, which is involved in de novo bacterial ceramide synthesis . It catalyses the condensation of 3-oxosphinganine with an acyl-CoA to generate oxidized ceramides . It may have a preference for monounsaturated acyl-CoA substrates, as it has a threefold greater preference for C16:1-CoA over C16:0-CoA as a substrate in vitro . The biosynthetic steps of ceramide synthesis in bacteria occur in a different order from that in eukaryotes and phylogenetic analyses suggest that the bacterial and eukaryotic ceramide pathways evolved independently . This entry also includes YghO from E. coli, whose function is unknown.
Transcription factor Grauzone (TF_Grauzone)
Type: Family

The zinc finger protein Grauzone is a transcription factor essential for the completion of meiosis in oocytes in Drosophila . Grauzone binds to the cortex promoter and is necessary for high-level activation of cortex transcription .
Pre-mRNA-splicing factor CWC24-like (CWC24-like)
Type: Family

This entry contains proteins with a CCCH-type zinc finger, which bind zinc via cysteine and histidine residues in the motif C-x8-C-x5-C-x3-H, and a C3HC4 type RING finger. Proteins with this structure include:

Pre-mRNA-splicing factor CWC24, a component of the CWC complex, which is involved in pre-mRNA splicing .

RING finger protein 113A, an E3 ubiquitin-protein ligase that catalyses polyubiquitination of SNRNP200/BRR2 with non-canonical 'Lys-63'-linked polyubiquitin chains and CXCR4, leading to its degradation and thereby termination of CXCR4 signalling .

RING finger protein 113B, which is uncharacterised.
Sarcoglycan gamma/delta/zeta (Sarcoglycan_gamma/delta/zeta)
Type: Family

The dystrophin glycoprotein complex (DGC) is a membrane-spanning complex that links the interior cytoskeleton to the extracellular matrix in muscle. The sarcoglycan complex is a subcomplex within the DGC and is composed of several muscle-specific, transmembrane proteins (alpha-, beta-, gamma-, delta- and zeta-sarcoglycan). The sarcoglycans are asparagine-linked glycosylated proteins with single transmembrane domains. This family contains beta, gamma, delta and zeta members .

This entry includes sarcoglycans gamma, delta and zeta.
Pre-mRNA-splicing factor SLU7 (Splicing_factor_SLU7)
Type: Family

The spliceosome, an assembly of snRNAs (U1, U2, U4/U6, and U5) and proteins, catalyses the excision of introns from pre-mRNAs in two successive trans-esterification reactions . Step 2 depends upon integral spliceosome constituents such as U5 snRNA and Prp8 and non-spliceosomal proteins Prp16, Slu7, Prp18, and Prp22. ATP hydrolysis by the DEAH-box enzyme Prp16 promotes a conformational change in the spliceosome that leads to protection of the 3' splice site from targeted RNase H cleavage. This change, which probably reflects binding of the 3' splice site PyAG in the catalytic centre of the spliceosome, requires the ordered recruitment of Slu7, Prp18, and Prp22 to the spliceosome. There is a close functional relationship between Prp8, Prp18, and Slu7, and Prp18 interacts with Slu7, so that together they recruit Prp22 to the spliceosome. Most members of the family carry a zinc-finger of the CCHC-type; this retains the protein within the nucleus .
Intraflagellar transport protein 52 homolog (IFT52)
Type: Family

This entry includes mammalian intraflagellar transport protein 52 homolog (IFT52) and its homologues from bacteria. IFT52 is a component of the IFT complex B complex required for the movement of components required for the assembly, maintenance and function of primary cilia. Transport occurs in both directions . Mutations in the IFT52 gene can lead to short-rib thoracic dysplasia 16 with or without polydactyly .
WPP domain-interacting tail-anchored protein (WIT1/WIT2)
Type: Family

WIT1 and WIT2 are tail-anchored proteins required for the nuclear envelope anchoring of RANGAP (Ran GTPase activating protein) in root tips in Arabidopsis . They could be involved in determining plant nuclear shape and pollen tube guidance .
Histone-lysine N-methyltransferase Suv4-20/Set9 (Suv4-20/Set9)
Type: Family

This entry includes Suv4-20 family members and its fungal homologue known as Set9. They are a group of histone H4K20 methyltransferases.

SET9 methylates 'Lys-20' of histone H4. H4 'Lys-20' methylation is apparently not involved in the regulation of gene expression or heterochromatin function, but participates in DNA damage response by giving a 'histone mark' required for the recruitment of the checkpoint protein Crb2 to sites of DNA damage .

Post-translational modification of the core histones H2A, H2B, H3 and H4 play an important part in chromatin biology. Histone H4 lysine 20 methylation (H4K20me) is critical for the biological processes that ensure genome integrity, such as DNA damage repair, DNA replication and chromatin compaction . Suv4-20 family members are a group of histone H4K20 methyltransferases that play an important role in epigenetic regulation. Lower eukaryotes have a single Suv4-20, while mammals have two closely related Suv4-20 paralogs, SUV420H1 and SUV420H2 . In mammals H4K20me2 is generated primarily by SUV420H1/KMT5B (which can also produce H4K20me3), while H4K20me3 is mostly generated by SUV420H2/KMT5C .
Pre-mRNA-splicing factor 18 (PRPF18)
Type: Family

The splicing factor Prp18 is required for the second step of pre-mRNA splicing. PRP18 appears to be primarily associated with the U5 snRNP.

The structure of a large fragment of the Saccharomyces cerevisiae Prp18 is known . This fragment is fully active in yeast splicing
in vitro
and includes the sequences of Prp18 that have been evolutionarily conserved. The core structure consists of five α-helices that adopt a novel fold. The most highly conserved region of Prp18, a nearly invariant stretch of 19 aa, forms part of a loop between two α-helices and may interact with the U5 small nuclear ribonucleoprotein particles .
MAP kinase-activating death domain protein (MADD)
Type: Family

MAP kinase-activating death domain protein (MADD) regulates cell proliferation, survival and death through alternative mRNA splicing. Different isoforms have different effects: isoform 5 increases cell proliferation whereas isoform 2 decreases it; isoform 1 is susceptible to inducing apoptosis, isoform 5 is resistant . MADD activates RAB3A, RAB3C and RAB3D by converting them from GDP-bound inactive forms to GTP-bound active forms . MADD is a component of the TNFRSF1A signaling complex, linking the type 1 tumor necrosis factor receptor TNFRSF1A with MAP kinase activation . MADD contains a tripartite DENN domain. In the nematode Caenorhabditis elegans, MADD is also known as regulator of presynaptic activity aex-3 .
Large ribosomal subunit protein mL65 (Ribosomal_mL65)
Type: Family

The entry includes the mitochondrial 28S ribosomal protein mL65 (also known as mitochondrial ribosomal protein MRP-S30), a component of the mitochondrial ribosome small subunit (28S) , and the mitochondrial 39S ribosomal protein mL65 (similarly known as mitochondrial ribosomal protein MRP-S30), a component of the mitochondrial large ribosomal subunit (mt-LSU) . The mature mammalian 55S mitochondrial ribosome consists of a small (28S) and a large (39S) subunit .
Cholesterol 24-hydroxylase (CYP46A1)
Type: Family

Cholesterol 24-hydroxylase (CYP46A1) is the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol (24S-OHC) . It has a neuroprotective effect in Huntington's disease, a genetic disease that leads to many cellular dysfunctions, including abnormalities in cholesterol metabolism .
Cilia- and flagella- associated protein 210 (CFAP210)
Type: Family

This family includes Cilia- and flagella- associated protein 210 (CFAP210, also known as Coiled-coil domain-containing protein 173) which appears to be a microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating .
PGR5-like protein 1 (PGRL1)
Type: Family

PGR5-like protein 1 (PGRL1) is involved in photosynthetic cyclic electron flow, which is driven by PSI (photosystem I). PGRL1 forms homodimers and PGRL1-PGR5 heterodimers. The PGR5-PGRL1 complex mediates the second photosynthetic cyclic electron transport (CET) circuit, accepting electrons from ferredoxin (Fd) and reducing the plastoquinone (PQ) pool, thus acting as an Fd-PQ reductase . In Arabidopsis thaliana, there are two orthologues, PGRL1A and PGRLB.
Microsomal triglyceride transfer protein large subunit (MTTP)
Type: Family

Microsomal triglyceride transfer protein large subunit (MTTP) catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces, and is required for the secretion of plasma lipoproteins that contain apolipoprotein B. It is a heterodimer consisting of a large MTP alpha-subunit and a protein disulfide isomerase (PDI) beta-subunit. Mutations in microsomal triglyceride transfer protein (MTP) cause abetalipoproteinemia .
ADP-ribose pyrophosphatase, mitochondrial (NUDT9)
Type: Family

Mitochondrial ADP-ribose pyrophosphatase (also known as nucleoside diphosphate-linked moiety X motif, nudix motif 9 or 9NUDT9) hydrolyzes ADP-ribose to AMP and ribose 5'-phosphate . 9NUDT9 interacts with GLOD4 . This entry also include putative nudix hydrolase 6 from Caenorhabditis elegans.
Protein shortage in chiasmata 1 ortholog (SHOC1)
Type: Family

Shortage in chiasmata 1 orthologue, the plant SHOC1 orthologue in animals, has been shown to act at mid-stage steps of the crossover (CO) formation process. It also interacts with TEX11, another protein important for the formation of COs. SHOC1 has associated ATPase activity, but lacks endonuclease activity, so it has been speculated that SHOC1 may protect against dissociation by anti-crossover activities instead of having a role in cleaving recombination intermediates to produce COs .
Selenoprotein F/M (Sep15_SelM)
Type: Family

Selenoprotein F (Sep15) and selenoprotein M (SelM) are eukaryotic selenoproteins that have a thioredoxin-like domain and a surface accessible active site redox motif . This suggests that they function as thiol-disulphide isomerases involved in disulphide bond formation in the endoplasmic reticulum .
NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 (NDUFB10)
Type: Family

This entry includes NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 (NDUFB10) and mitochondrial NADH-ubiquinone oxidoreductase 12kDa subunit (also known as NDUS6).

NADH-ubiquinone oxidoreductase subunit 10 of (NDUFB10) is a member of a family of conserved proteins of up to 180 residues. It is one of the 41 protein subunits within the hydrophobic fraction of the NADH:ubiquinone oxidoreductase (complex I), a multiprotein complex located in the inner mitochondrial membrane whose main function is the transport of electrons from NADH to ubiquinone, which is accompanied by translocation of protons from the mitochondrial matrix to the intermembrane space. NDUFB10 is encoded in the nucleus .

NADH dehydrogenase [ubiquinone] iron-sulphur protein 6 subunit is an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain and is composed of about 45 subunits. The immediate electron acceptor for the enzyme is believed to be ubiquinone.
Histone lysine demethylase/ribosomal histidine hydroxylase NO66-like (NO66-like)
Type: Family

This entry includes proteins with a JmjC domain. Proteins are bifunctional, acting as histone lysine demethylases and ribosomal histidine hydroxylases. Proteins include:

Bifunctional lysine-specific demethylase and histidyl-hydroxylase NO66 (also known as Jumanjic domain protein 1) .

Ribosomal oxygenase 1 (also known as ribosomal oxygenase NO66), which specifically demethylates 'Lys-4' (H3K4me) and 'Lys-36' (H3K36me) of histone H3 .

Ribosomal oxygenase 2, which demethylates trimethylated 'Lys-9' on histone H3 (H3K9me3), leading to an increase in ribosomal RNA expression . It also hydroxylates 60S ribosomal protein L27a on 'His-39' .

50S ribosomal protein L16 3-hydroxylase from Escherichia coli (also known as Ribosomal protein uL16 3-hydroxylase), which catalyses the hydroxylation of 50S ribosomal protein L16 on 'Arg-81' .

The JmjN and JmjC domains are two non-adjacent domains which have been identified in the jumonji family of transcription factors. Although it was originally suggested that the JmjN and JmjC domains always co-occur and might form a single functional unit within the folded protein, the JmjC domain was later found without the JmjN domain in organisms from bacteria to human .

Proteins containing JmjC domain are predicted to be metalloenzymes that adopt the cupin fold and are candidates for enzymes that regulate chromatin remodelling . The cupin fold is a flattened β-barrel structure containing two sheets of five antiparallel β-strands that form the walls of a zinc-binding cleft. Based on the crystal structure of JmjC domain containing protein FIH and JHDM3A/JMJD2A, the JmjC domain forms an enzymatically active pocket that coordinates Fe(III) and alphaKG. Three amino-acid residues within the JmjC domain bind to the Fe(II) cofactor and two additional residues bind to alphaKG .

JmjC domains were identified in numerous eukaryotic proteins containing domains typical of transcription factors, such as PHD, C2H2, ARID/BRIGHT and zinc fingers . The JmjC has been shown to function in a histone demethylation mechanism that is conserved from yeast to human . JmjC domain proteins may be protein hydroxylases that catalyse a novel histone modification . The human JmjC protein named Tyw5p unexpectedly acts in the biosynthesis of a hypermodified nucleoside, hydroxy-wybutosine, in tRNA-Phe by catalysing hydroxylation .
Peroxisomal biogenesis factor 39 (PEX39)
Type: Family

This entry represents the human Peroxisomal biogenesis factor 39 (PEX39) and related proteins mainly found in mammals. PEX39 is probably a peroxin involved in the PTS2-mediated protein import pathway .
Shieldin complex subunit 3 (Shieldin_RINN1)
Type: Family

RINN1 is a component of the shieldin complex, together with RINN2, RINN3 and REV7. The shieldin complex plays an important role in repair of DNA double-stranded breaks (DSBs) . Recruitment of shieldin to DSBs promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination, and fusion of unprotected telomeres .
Transcription factor E (TFE)
Type: Family

Initiation of eukaryotic mRNA transcription requires melting of promoter DNA with the help of the general transcription factors TFIIE and TFIIH. In higher eukaryotes, the general transcription factor TFIIE consists of two subunits: the large alpha subunit (

) and the small beta (

). TFIIE beta has been found to bind to the region where the promoter starts to open to be single-stranded upon transcription initiation by RNA polymerase II. The approximately 120-residue central core domain of TFIIE beta plays a role in double-stranded DNA binding of TFIIE .

The TFIIE β-central core DNA-binding domain consists of three helices with a β-hairpin at the C terminus, resembling the winged helix proteins. It shows a novel double-stranded DNA-binding activity where the DNA-binding surface locates on the opposite side to the previously reported winged helix motif by forming a positively charged furrow .

Archaea contain a TFIIE homologue, called TFE, which corresponds to the N-terminal half of TFIIEalpha. It appears that archaeal TFE corresponds to the minimal essential region of eukaryotic TFIIEalpha. In archaea TFE contains an N-terminal, weakly conserved, helix-turn-helix (HTH) motif within a leucine-rich region and a C-terminal zinc ribbon . It has been proposed that the TFE/IIEalpha-type HTH domain acts as a bridging factor or adapter between the TATA box-binding protein, the polymerase, and possibly promoter DNA .

The TFE/IIEalpha-type HTH domain adopts a winged HTH (winged helix) fold, comprising three α-helices and three β-strands in the canonical order α1-β1-α2-α3-β2-β3. Conserved residues within helices α1-α3 form the tightly packed hydrophobic core of the winged helix domain. A specific feature of the structure is the extension of the canonical winged helix fold at the N and C termini by the additional helices α0 and α4, respectively. Hydrophobic residues from the additional helix α0 extend the hydrophobic core of the winged helix domain, and helix α0 is tightly packed against the canonical winged helix fold. Helix alpha4 comprises only one turn .
Cell growth-regulating nucleolar protein (LYAR)
Type: Family

Proteins in this family contain a C2H2, LYAR-type zinc finger. Included in this family is cell growth-regulating nucleolar protein (LYAR), which maintains the appropriate processing of 47S/45S pre-rRNA to 32S/30S pre-rRNAs and their subsequent processing to produce 18S and 28S rRNAs . It is also a repressor of the gamma-globin promoter and oxidative stress genes .