SII-SWORD/CoKE huggingface dataset:
Inactive serine/threonine-protein kinase TEX14 (Tex14)
Type: Family

TEX14 is an inactive serine/threonine-protein kinase because the active site aspartic acid residue has been replaced. It localizes to germ cell intercellular bridges during spermatogenesis. In germ cell cytokinesis a permanent intercellular bridge connecting the daughter cells through a large cytoplasmic channel forms, unlike in somatic cells. This bridge does not form in TEX14 deficient mice and male mice are sterile ; female knockout mice are fertile . TEX14 binds to CEP55, which is a stable component of the intercellular bridge, via a GPPX3Y motif and preventing proteins with a similar motif (such as ALIX and TSG101) from binding to CEP55 . During mitosis, TEX14 is recruited to kinetochores by Plk1 and without TEX14, kinetochores are unable to bind other essential components leading to chromosome instability. Phosphorylation of TEX14 by Plk1 leads to its degradation, which is essential for metaphase-to-anaphase transition and chromosome segregation . TEX14 contains ankyrin repeat-containing domains and a protein kinase domain.
Transcription factor Tfc4/TFIIIC-102/Sfc4 (Tfc4/TFIIIC-102/Sfc4)
Type: Family

TFIIIC-102, also known as general transcription factor 3C polypeptide 3 (GTF3C3), is required for RNA polymerase III-mediated transcription and is a component of the DNA-binding TFIIIC2 subcomplex that directly binds tRNA and virus-associated RNA promoters . GTF3C3 contains several tetratricopeptide repeats.

In Saccharomyces cerevisiae, this protein is known as transcription factor tau 131kDa subunit (Tfc4). It is the TFIIIB-assembling subunit of RNA polymerase III transcription initiation factor complex (TFIIIC) . In Schizosaccharomyces pombe, this subunit is known as Sfc4 .
Cilia- and flagella-associated protein 99 (CFAP99)
Type: Family

The function of CFAP99 is not clear.
Protein TRIGALACTOSYLDIACYLGLYCEROL 2-like (TGD2-like)
Type: Family

This entry represents a group of proteins mostly from Cyanobacteria (blue-green algae) and plants, including TRIGALACTOSYLDIACYLGLYCEROL 2 (TGD2) from Arabidopsis. TGD2 is a component of a phosphatidic acid/lipid transport complex in the chloroplast envelope . Proteins in this entry contain a Mce/MlaD domain.
Protein NEOXANTHIN-DEFICIENT 1-like (NDX1-like)
Type: Family

This entry represents a group of proteins mostly from plants and Cyanobacteria (blue-green algae), including protein NEOXANTHIN-DEFICIENT 1 (NDX1) from tomato. NDX1 is involved in neoxanthin biosynthesis .
Metallo-beta-lactamase domain-containing protein 1 (MBLAC1)
Type: Family

This family includes metallo-beta-lactamase domain-containing protein 1 (MBLAC1), an endoribonuclease that catalyses the hydrolysis of histone-coding pre-mRNA 3'-end. It is involved in histone pre-mRNA processing during the S-phase of the cell cycle, which is required for entering/progressing through S-phase.
Classical arabinogalactan protein 25/26 (AGP25/26)
Type: Family

Arabinogalactan-proteins (AGPs) are cell wall proteoglycans and are widely distributed in the plant kingdom. They have a predicted glycosylphosphatidylinositol lipid anchor and are suggested to be involved in cell-cell signaling . This entry includes AGP25 and AGP26 from Arabidopsis.
Sperm mitochondrial-associated cysteine-rich protein (SMCP)
Type: Family

This entry includes sperm mitochondrial cysteine-rich protein (SMCP) from human, which enhances sperm motility . Its absence has been associated with infertility.
Protein PLASTID REDOX INSENSITIVE 2 (PRIN2)
Type: Family

This entry represents a group of plant proteins, including PRIN2 (Protein PLASTID REDOX INSENSITIVE 2) from Arabidopsis. PRIN2 is a chloroplastic protein essential for proper plant embryo development . It is localized to the plastid nucleoids and is required for full expression of genes transcribed by PEP (plastid encoded RNA polymerase), an enzyme that predominantly mediates the transcription of photosynthesis-related genes .
Prospero homeodomain family (Prospero_homeodomain)
Type: Family

Prospero-related proteins are conserved among metazoa and play important roles in development. They contain two characteristic conserved domains termed prospero domain 1 (PD1) and PD2 . Drosophila Pros plays well-known roles in the establishment of cell fate during nervous system development . In C. elegans, Prox1 functions as a major regulator of the glia-specific secretome that controls shape and function of sensory neurons . Vertebrate Prox1 plays divergent roles in multiple organs by associating with nuclear receptors and modulating their transcriptional activities . A second member of the family, Prox2, is present in vertebrates .
Keratin-associated protein 8-1 (KRTAP8-1)
Type: Family

The keratin-associated proteins (KAPs) are fundamental components of hair and wool fibres . This entry represents KRTAP8-1, which is a high sulphur (HS) KAP .
Protein BEAN1 (BEAN1)
Type: Family

The function of BEAN1 (brain expressed, associated with Nedd4) is not clear. Mutations in the BEAN1 gene cause spinocerebellar ataxia type 31 (SCA31), an autosomal-dominant cerebellar ataxia showing a Purkinje cell (PC)-predominant neurodegeneration in humans .
Transcription factor Adf-1 (TF_Adf1)
Type: Family

This family of transcription factors may play an important role in the regulation of Adh expression and other genes .
Transcription factor GATA (Transcription_factor_GATA)
Type: Family

This entry represents proteins with GATA-type zinc fingers (Znf). A number of transcription factors (including erythroid-specific transcription factor and nitrogen regulatory proteins) specifically bind the DNA sequence (A/T)GATA(A/G) in the regulatory regions of genes. They are consequently termed GATA-binding transcription factors. The interactions occur via highly-conserved Znf domains in which the zinc ion is coordinated by four cysteine residues . NMR studies have shown the core of the Znf to comprise two irregular anti-parallel β-sheets and an α-helix, followed by a long loop to the C-terminal end of the finger. The N-terminal part, which includes the helix, is similar in structure, but not sequence, to the N-terminal zinc module of the glucocorticoid receptor DNA-binding domain. The helix and the loop connecting the two β-sheets interact with the major groove of the DNA, while the C-terminal tail wraps around into the minor groove. It is this tail that is the essential determinant of specific binding. Interactions between the Znf and DNA are mainly hydrophobic, explaining the preponderance of thymines in the binding site; a large number of interactions with the phosphate backbone have also been observed . Two GATA zinc fingers are found in the GATA transcription factors. However there are several proteins which only contains a single copy of the domain.

The GATA-type transcription factors SreA and Sre1 from fungi regulate iron- acquisition genes .
5'-deoxynucleotidase YfbR/HDDC2 (YfbR/HDDC2)
Type: Family

Escherichia coli YfbR is a conserved HD-domain-containing protein with orthologues found in bacteria, archaea, and eukaryotes. YfbR shows strict specificity towards deoxyribonucleoside 5'-monophosphates , and has been established as an essential component of the deoxycytidine pathway for de novo synthesis of thymidylate . The human genome encodes one YfbR orthologue, the uncharacterised HD-domain-containing protein HDDC2. In yeast, HD-domain proteins YGK1 (YGL101W) and YB92 (YBR242W) from Saccharomyces cerevisiae are nucleoside 5'-monophosphatases, with substrate preference for deoxyribonucleoside 5'-monophosphatase over ribonucleoside 5'-monophosphatase .
3-oxo-5-alpha-steroid 4-dehydrogenase/very-long-chain enoyl-CoA reductase (SRD5A/TECR)
Type: Family

3-oxo-5-alpha-steroid 4-dehydrogenases (

) catalyse the conversion of 3-oxo-5-alpha-steroid + acceptor to 3-oxo-delta(4)-steroid + reduced acceptor. The steroid 5-alpha-reductase enzyme is responsible for the formation of dihydrotestosterone, this hormone promotes the differentiation of male external genitalia and the prostate during foetal development . In humans mutations in this enzyme can cause a form of male pseudohermaphorditism in which the external genitalia and prostate fail to develop normally. A related steroid reductase enzyme, DET2, is found in plants such as Arabidopsis. Mutations in this enzyme cause defects in light-regulated development .

Another enzyme in this entry is very-long-chain enoyl-CoA reductase (TECR;

), which catalyzes the last of the four reactions of the long-chain fatty acids elongation cycle by reducing the trans-2,3-enoyl-CoA fatty acid intermediate to an acyl-CoA that can be further elongated by entering a new cycle of elongation .
Ras GTPase-activating protein (Ras_GTPase)
Type: Family

Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP . This intrinsic GTPase activity of Ras is regulated by a family of proteins collectively known as 'GAP' or GTPase-activating proteins . RasGAP proteins are usually quite large (from 765 residues for sar1 to 3079 residues for IRA2) but share only a limited (about 250 residues) region of sequence similarity, referred to as the 'catalytic domain' or RasGAP domain. The most conserved region within this domain contains a 15 residue motif which seems to be characteristic of this family of proteins .
Cyclin (Cyclin)
Type: Family

Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles , and regulate cyclin dependent kinases (CDKs). Cyclins, together with the p34 (cdc2) or cdk2 kinases, form the Maturation Promoting Factor (MPF). There are two main groups of cyclins, G1/S cyclins, which are essential for the control of the cell cycle at the G1/S (start) transition, and G2/M cyclins, which are essential for the control of the cell cycle at the G2/M (mitosis) transition. G2/M cyclins accumulate steadily during G2 and are abruptly destroyed as cells exit from mitosis (at the end of the M-phase). In most species, there are multiple forms of G1 and G2 cyclins. For example, in vertebrates, there are two G2 cyclins, A and B, and at least three G1 cyclins, C, D, and E.

Cyclin homologues have been found in various viruses, including Saimiriine herpesvirus 2 (Herpesvirus saimiri) and Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus). These viral homologues differ from their cellular counterparts in that the viral proteins have gained new functions and eliminated others to harness the cell and benefit the virus .
Autophagy-related protein 29 superfamily (ATG29_sf)
Type: Homologous_superfamily

Autophagy-related (Atg) proteins play a role in autophagy. Atg29 forms a complex with Atg17 and Atg31. When autophagy is initiated, the Atg17-Atg31-Atg29 complex is first targeted to the phagophore assembly site (PAS) and then recruits other Atg proteins . The complex is recruited to the PAS by Atg11. Atg29 contains an N-terminal functional domain, whereas the C terminus plays a regulatory role. Phosphorylation of the C-terminal domain of Atg29 is required for its interaction with Atg11 and proper PAS localization .

The tertiary structure of Atg29 (within the Atg17-Atg29-Atg31 subcomplex) has been determined in part, showing a central three-helix bundle .
Zinc finger protein 750 (ZNF750)
Type: Family

ZNF750 is a transcription factor that controls epithelial homeostasis by inhibiting progenitor genes while inducing differentiation genes . ZNF750 and related proteins contain a zinc finger domain. Human proline-rich protein 35 is related, but its function is not clear.
Transposase IS701-like (IS701-like)
Type: Family

This entry represents a group of transposase IS701-like proteins. They have a DDE domain containing three carboxylate residues that are believed to be responsible for coordinating metal ions needed for catalysis. The catalytic activity of this enzyme involves DNA cleavage at a specific site followed by a strand transfer reaction . IS701 is predicted to have a β-strand insertion domain .
Type 3 secretion system pilotin (Pilotin)
Type: Family

The type III secretion system (T3SS) is a macromolecular machinery that inject toxins directly into the cytoplasm of target cells .

This entry includes outer membrane lipoproteins such as Pilotin (also known as Exoenzyme S synthesis protein B, or ExsB) that are involved in the T3SS assembly .
Initiation-specific alpha-1,6-mannosyltransferase Och1-like (Och1-like)
Type: Family

This entry includes Och1 and its homologue, Hoc1. Och1 is a alpha-1,6-mannosyltransferase involved in the N-linked oligosaccharide modification in the Golgi apparatus with the addition of mannose to the Man
8
GlcNAc
2
or Man
9
GlcNAc
2
endoplasmic reticulum intermediates . Hoc1 is a subunit of the M-Pol II complex and possesses alpha-1,6-mannosyltransferase activity .
Acetolactate synthase large subunit, TPP binding domain (AHAS_TPP)
Type: Domain

This entry represents the thiamine pyrophosphate (TPP) binding domain found in the acetohydroxyacid synthase (AHAS) subfamily members. AHAS catalyzes the condensation of two molecules of pyruvate to give the acetohydroxyacid, 2-acetolactate. 2-Acetolactate is the precursor of the branched chain amino acids, valine and leucine. AHAS also catalyzes the condensation of pyruvate and 2-ketobutyrate to form 2-aceto-2-hydroxybutyrate in isoleucine biosynthesis. In addition to requiring TPP and a divalent metal ion as cofactors, AHAS requires FAD .
Galactoside O-acetyltransferase LacA-like (LacA-like)
Type: Family

This entry includes a group of acetyltransferases, including LacA from E. coli and YJL218W from budding yeast. LacA is a galactoside O-acetyltransferase .
Transcription factor BTF3 (BTF3)
Type: Family

In eukaryotes, the Nascent polypeptide-Associated Complex (NAC) is a heterodimeric cytosolic protein complex composed of NAC alpha (NACA) and NAC beta (BTF3) . NAC binds reversibly to the ribosome where it is in contact with nascent chains as they emerge from the ribosome. But the cellular function of NAC seems to be much more diverse as it is also involved in transcription regulation and mitochondrial translocation . Alpha and beta NACs share homology with each other, both contain a NAC A/B domain. In archaea no beta NAC proteins are found; the complex is an homodimer of NAC alpha .

The crystal structure of an archeal NAC has been solved . The NAC A/B domain consists of six strands arranged in a β-barrel structure similar to the OB fold. Various OB folds interact with ribosomal RNA which could suggest a similar role for the NAC A/B domain.

This entry represents the mammalian transcription factor BTF3, which is a component of the nascent polypeptide-associated complex (NAC) . In yeast, this component is known as nascent polypeptide-associated complex subunit beta-1 (or EGD1) .
LeuA, N-terminal catalytic TIM barrel domain (LeuA_N_DRE-TIM)
Type: Domain

Alpha-isopropylmalate synthase (LeuA), a key enzyme in leucine biosynthesis, catalyzes the first committed step in the pathway, converting acetyl-CoA and alpha-ketoisovalerate to alpha-isopropyl malate and CoA . Although the reaction catalyzed by LeuA is similar to that of the Arabidopsis thaliana IPMS1 protein, the two fall into phylogenetically distinct families within the same superfamily.

LeuA has and N-terminal TIM barrel catalytic domain, a helical linker domain, and a C-terminal regulatory domain. LeuA forms a homodimer in which the linker domain of one monomer sits over the catalytic domain of the other, inserting residues into the active site that may be important for catalysis . Homologues of LeuA are found in bacteria as well as fungi, such as alpha-isopropylmalate synthases I (LEU4) and II (LEU9) from Saccharomyces cerevisiae .
Transferrin receptor protein 1/Glutamate carboxypeptidase 2-like (Peptidase_M28B)
Type: Family

This entry includes glutamate carboxypeptidase 2 (FOLH1) and its homologues from peptidase family M28 subfamily B. Not all members of this subfamily are peptidases, and non-peptidase homologues include transferrin receptor proteins (TFRC).

FOLH1 is a zinc-dependent carboxypeptidase that also acts as a folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase). It has a preference for tri-alpha-glutamate peptides . It is required for the uptake of folate in the intestine, and in the brain modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), releasing glutamate. Two zinc ions are bound per molecule .

TFRC acts as a lipid sensor, controlling the fusion of mitochondria by modulating the activation of the JNK pathway .
Siderophore-interacting protein (SIP_fam)
Type: Family

Siderophores are produced in various bacteria (and some plants) to extract iron from hosts. This entry represents a group of siderophore-interacting proteins, including ViuB and VuuB from Vibrio cholerae and YqjH from E. coli. ViuB is a putative siderophore-interacting protein (SIP) , functionally substituted for the E. coli ferric reductase YqjH, which promotes the release of iron from the siderophore in the bacterial cytoplasm . VuuB is a ferric-siderophore reductase involved in iron removal from the siderophores after their transport into the cell. It acts as a major ferric-vulnibactin reductase catalysing the reduction of Fe3+-vulnibactin, a catecholate siderophore synthesized by V.vulnificus. It catalyses reduction of Fe3+-aerobactin, a citrate-hydroxamate siderophore produced by other bacteria, in the absence of IutB .
Nodulation protein N-like (NodN-like)
Type: Family

NodN (nodulation factor N) contains a single hot dog fold similar to those of the peroxisomal Hydratase-Dehydrogenase-Epimerase (HDE) protein, and the fatty acid synthase beta subunit . Rhizobium and related species form nodules on the roots of their legume hosts, a symbiotic process that requires production of Nod factors, which are signal molecules involved in root hair deformation and meristematic cell division. The nodulation gene products, including NodN, are involved in producing the Nod factors, however the role played by NodN is unclear .
Ferritin-like, di-iron-binding domain (Ferritin_CCC1_N)
Type: Domain

This domain present in an uncharacterised family of proteins found in bacteria and archaea. These proteins also have a C-terminal CCC1-like transmembrane domain and are thought to be involved in iron and/or manganese transport. This domain has the conserved residues of a di-iron centre found in other ferritin-like proteins .
Manganese catalase, ferritin-like di-iron-binding domain (Mn_catalase_dom)
Type: Domain

Manganese (Mn) catalase is a member of a broad superfamily of ferritin-like di-iron enzymes . While many di-iron enzymes catalyze dioxygen-dependent reactions, manganese catalase performs peroxide-dependent oxidation-reduction. Catalases are important antioxidant metalloenzymes that catalyze disproportionation of hydrogen peroxide, forming dioxygen and water. Manganese catalase, a nonheme type II catalase, contains a binuclear manganese cluster that catalyzes the redox dismutation of hydrogen peroxide, interconverting between dimanganese(II) [(2,2)] and dimanganese(III) [(3,3)] oxidation states during turnover . Mn catalases are found in a broad range of microorganisms in microaerophilic environments, including the mesophilic lactic acid bacteria (e.g., Lactobacillus plantarum) and bacterial and archaeal thermophiles (e.g., Thermus thermophilus and Pyrobaculum caldifontis). L. plantarum and T. thermophilus holoenzymes are homohexameric structures; each subunit contains a dimanganese active site. The manganese ions are linked by a mu 1,3-bridging glutamate carboxylate and two mu-bridging solvent oxygens that electronically couple the metal centres .
Ribonuclease T2, prokaryotic (RNase_T2_prok)
Type: Family

Ribonuclease T2 (RNase T2) is a widespread family of secreted RNases found in every organism examined thus far. This family includes RNase Rh, RNase MC1, RNase LE, and self-incompatibility RNases (S-RNases) . Plant T2 RNases are expressed during leaf senescence in order to scavenge phosphate from ribonucleotides. They are also expressed in response to wounding or pathogen invasion. S-RNases are thought to prevent self-fertilization by acting as selective cytotoxins of "self" pollen. Generally, RNases have two distinct binding sites: the primary site (B1 site) and the subsite (B2 site), for nucleotides located at the 5'- and 3'- terminal ends of the sissile bond, respectively.

This entry includes the prokaryotic RNase T2 family members.
Protoglobin, globin sensor domain (Protoglobin_sensor_dom)
Type: Domain

This entry represents the globin sensor domain found in protoglobin from Archaea. Protoglobin has specific loops and an amino-terminal extension which leads to the burying of the haem within the matrix of the protein. Protoglobin-specific apolar tunnels allow the access of O
2
, CO and NO to the haem distal site . This domain is also found in the N-terminal regions of HemAT from the archaeon Halobacterium salinarum (HemAT-Hs) and from the Gram-positive bacterium Bacillus subtilis (HemAT-Bs). It contains a myoglobin-like motif, displays characteristic heme-protein absorption spectra, and binds oxygen reversibly .
Toxin-ParB-like (Toxin-ParB-like)
Type: Domain

This entry represents a toxin domain with similarity to the N-terminal domain of ParB, a DNA-binding component of the prokaryotic parABS partitioning system and related proteins . Toxins are found at the C terminus of polymorphic toxin system members .
Endopeptidase La, PDZ domain (La_PDZ)
Type: Domain

This entry represents the PDZ domain of ATP-dependent LON (also known as La) serine proteases (peptidase family S16). Most PDZ domains bind C-terminal polypeptides, though binding to internal (non-C-terminal) polypeptides and even to lipids has been demonstrated. In this bacterial subfamily of protease-associated PDZ domains a C-terminal β-strand is thought to form the peptide-binding groove base, a circular permutation with respect to PDZ domains found in Eumetazoan signaling proteins .
Protease Do-like 1/8, PDZ domain (DEGP1/8_PDZ_dom)
Type: Domain

This entry represents the PDZ domain of Arabidopsis thaliana DEGP1 (also known as protease Do-like 1, chloroplastic, protein DEGRADATION OF PERIPLASMIC PROTEINS 1, DEGP PROTEASE 1 and DEG1) and DEGP8. DEGP1 is a serine protease that is required at high temperature and may be involved in the degradation of damaged proteins . DEGP8/Do-like 8 (chloroplastic), is a probable serine protease. It forms a hexamer with DEG5 in the thylakoid lumen and it is involved in the cleavage of photodamaged D2 protein of photosystem II (PSII) . PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal of their partner proteins (known as PDZ binding motifs).
FHIT family (FHIT)
Type: Family

FHIT (fragile histidine) proteins are related to the HIT family members that carry a motif HxHxH/Qxx (x, is a hydrophobic amino acid) . On the basis of sequence, substrate specificity, structure, evolution and mechanism, HIT proteins are classified into three branches: the Hint branch, which consists of adenosine 5' -monophosphoramide hydrolases, the FHIT branch, that consists of diadenosine polyphosphate hydrolases, and the GalT branch consisting of specific nucloside monophosphate transferases . FHIT plays a very important role in the development of tumours. In fact, FHIT deletions are among the earliest and most frequent genetic alterations in the development of tumours .