SII-SWORD/CoKE huggingface dataset:
Protein naked cuticle-like (Nkd-like)
Type: Family

This entry includes protein naked cuticle (Nkd) and its homologues from animals. Nkd is an evolutionarily conserved inducible antagonist of Wnt/beta-catenin signaling. Nkd is essential for segmentation in Drosophila melanogaster. It contains an unconventional nuclear localization motif essential for its function and nuclear localization .
ZPR1 (ZPR1)
Type: Family

This entry consists of zinc finger protein ZPR1 and ZPR1-like proteins. The function of ZPR1 from archaea and eukaryotes is not yet clear. However, Zpr1 from yeast acts as a protein folding chaperone for elongation factor 1-alpha . ZPR1 is present in both the cytoplasm and nucleoplasm and its subcellular distribution changes during proliferation . ZPR1 binds to the cytoplasmic tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and is a component of downstream signalling of both EGFR and FGFR signalling . Upon stimulation by EGF, ZPR1 directly binds the eukaryotic translation elongation factor-1alpha (eEF-1alpha) to form ZPR1/eEF-1alpha complexes, an interaction that is essential for normal cellular proliferation . It has been associated with susceptibility to type 2 diabetes and is downregulated in patients with spinal muscular atrophy . ZPR1 interacts with complexes formed by SMN , and may act as a modifier that affects the severity of SMA.
Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1)
Type: Family

This family consists of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1, SmgGDS) from vertebrates and its homologues from fungi and Drosophila, GTPase-GDP dissociation stimulator vimar. RAP1GDS1 acts as a guanine exchange factor (GEFs) acting on small GTPases RhoA and RhoC through a distinct exchange mechanism compared with canonical GEFs . RAP1GDS1 promotes both cell proliferation and migration and is up-regulated in several types of cancer . RAP1GDS1 plays a role in mitochondria morphology, as it regulates mitochondrial dynamics by controlling RHOT function to promote mitochondrial fission during high calcium conditions .
Integral membrane protein 2 (ITM2)
Type: Family

The family of type 2 integral membrane protein (ITM2) consists of three members, ITM2A, ITM2B and ITM2C . Members of this family contain a BRICHOS domain, which possesses chaperone activity .

ITM2A is a target gene of GATA-3, a T cell-specific transcription factor .

ITM2B is proteolytically cleaved at three locations; cleavage by furin in the C-terminal region generates a 23-residue peptide (ABri23), processing by ADAM10 results in release of the BRICHOS domain from the membrane-bound N-terminal part and intramembrane cleavage by SPPL2a/2b liberates the intracellular domain . ITM2B (BRI2) is a target of BCL6 transcriptional repression and a short form of the ITM2B protein, similarly to other targets of BCL6, induces apoptosis in hematopoietic cell lines . ITM2B interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production . ITM2C (BRI3) also inhibits amyloid precursor protein processing, but through a different mechanism to ITM2B .
Fragile X messenger ribonucleoprotein 1 (FMR1)
Type: Family

Fragile X messenger ribonucleoprotein 1 (FMRP/FMR1), and its paralogues, FXR1 and FXR2 (RNA-binding protein FXR1 and 2, respectively), comprise a family of RNA-binding proteins . They are highly similar to one another and also retain highly conserved domain architecture comprising two tandem Tudor Agenet-like domains at the N-terminal, three ribonucleoprotein K homology (KH) domains and a cluster of arginine and glycine residues that constitute the RGG box .

FMR1 protein is a multifunctional polyribosome-associated protein that plays a central role in neuronal development and synaptic plasticity. It regulates alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs . FMR1 is thought to bind target mRNA in the nucleus to form a ribonucleoprotein complex which is transported to dendrites and spines . It is also required for ovary development and function . FMR1 has also been shown to interact with components of the miRNA pathway . A large expansion of the CGG trinucleotide repeat in the 5'-untranslated region of the FMR1 gene causes Fragile X syndrome (FXS), an inherited developmental disorder that causes a broad range of intellectual and physical challenges .

FXR1 and FXR2 interact with FMR1 and seem to have a related role; therefore they are likely to play important roles in the function of FMR1 and in the pathogenesis of the FXS syndrome . FXR1 is highly expressed in vertebrates muscle cells and is required for proper development of this tissue .
RNA polymerase II nuclear localization protein Iwr1 (Iwr1)
Type: Family

Budding yeast Iwr1 binds to Pol II and directs its nuclear import . It also plays an important role in preinitiation complex formation by all three nuclear RNA polymerases .
Gfd2/YDR514C-like (Gfd2/YDR514C-like)
Type: Family

This entry includes a group of uncharacterised proteins mostly from fungi, including Gfd2 and YDR514C from budding yeasts .
ATPase synthesis protein 25, mitochondrial (Atp25)
Type: Family

Atp25 is a nuclear protein required for expression and assembly of the Atp9 (also known as Oli1) subunit of mitochondrial ATPase .
Respiratory supercomplex factor 2, mitochondrial (Rcf2)
Type: Family

Rcf2 is a subunit of cytochrome c oxidase that plays a role in assembly of respiratory supercomplexes .
Biotinidase/VNN family (Biotinidase/VNN)
Type: Family

Biotinidase catalyses the hydrolysis of biocytin, the product of biotin-dependent carboxylase degradation, to biotin and lysine. Biotinidase deficiency is an inherited metabolic disorder of biotin recycling that is characterised by neurological and cutaneous abnormalities, and can be successfully treated with biotin supplementation .

Pantetheinase is an enzyme that hydrolyses pantetheine, an intermediate metabolite of coenzyme A, into pantothenic acid (vitamin B5) and cysteamine. The pantetheinase family consists of pantetheinase/vanin-1/VNN1, GPI-80/VNN2 and vanin-3/VNN3. VNN2 and VNN3 are expressed in human leukocytes .

Both mammalian biotinidase and pantetheinase share a carbon-nitrogen hydrolase domain with significant similarity to the photoprotein from oceanic squid symplectin .
CEBPZ/Mak21-like (CEBPZ/Mak21-like)
Type: Family

This represents CAATT-binding proteins and their homologues, including Mak21 from budding yeasts, protein SLOW WALKER2 (SWA2) from Arabidopsis and CEBPZ from human and its orthologue from Drosophila Nucleolar complex protein 1 (Noc1). Mak21, also known as Noc1, is required for 60 S ribosomal subunit biogenesis . Together with Rrp5 and Noc2, Mak21 forms a protein module which is part of early large ribosomal subunit precursors . SWA2 may play a role in ribosome biogenesis and is essential for coordinated cell cycle progression during female gametophyte development in Arabidopsis . CEBPZ, the human homologue, regulates Hsp70 expression . Noc1 from Drosophila is involved in rRNA processing and ribosome maturation.
Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO)
Type: Family

Electron-transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein which is located in the mitochondrial matrix and reduces ubiquinone in the mitochondrial membrane. The two redox centres in the protein, FAD and a [4Fe4S] cluster, are present in a 64kDa monomer .

This family also includes probable electron transfer flavoprotein-ubiquinone oxidoreductases from bacteria.
Max dimerization protein 1, basic Helix-Loop-Helix-zipper domain (MXD1_bHLHzip)
Type: Domain

MXD1, also known as MAD, binds Max to form a repressive transcription factor. It antagonizes MYC transcriptional activity by competing for MAX . It has also been shown to regulate rRNA synthesis .

This entry represents the basic Helix-Loop-Helix-zipper (bHLHzip) domain of MXD1. The N-terminal basic region of this domain mediates high-affinity DNA-binding to specific hexanucleotide sequences .
Suppressor of hairless-like (CLS_fam)
Type: Family

The CLS family (CBF1/RBP-Jkappa/suppressor of hairless) consists of transcription factors essential for metazoan development, mainly due to their involvement in the Notch pathway . The members of this family recognize and bind to response element (GTGA/GGAA) in the promoters of the genes they regulate . Despite lacking the Notch pathway, CSL family members have been identified in fungal species. Schizosaccharomyces pombe has two CLS family proteins, Cbf11 and Cbf12, that bind the canonical CSL response element and play opposing roles in cell adhesion and coordination of cell and nuclear division .
Eukaryotic translation initiation factor 4E-binding protein Mextli (Mxt)
Type: Family

Mextli is a translation initiation factor 4E-binding protein that plays a role in promoting translation .
F-box A protein FB224 (FB224)
Type: Family

This entry includes a group of F-box proteins from Caenorhabditis, including FB224. Their function is not clear.
Microsomal glutathione S-transferase 1-like (MGST1-like)
Type: Family

Microsomal glutathione S-transferase 1 (MGST1) acts both as a glutathione transferase activity as well as in the reduction of various hydroperoxides, being important in the protection against oxidative stress . MGST1 is essential for embryonic development and hematopoiesis in vertebrates . Prostaglandin E synthase, also known as MGST1-like 1, catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) .

This entry also includes putative glutathione S-transferase-like proteins from bacteria.
High mobility group nucleosome-binding domain-containing protein 5 (HMGN5)
Type: Family

HMGN5, also known as NBP-45, binds to nucleosomes via its nucleosomal binding domain (NBD), unfolds chromatin, and affects transcription . It binds preferentially to euchromatin and modulates the fidelity of the cellular transcription by counteracting linker histone-mediated chromatin compaction .
Delta(24)-sterol reductase (Diminuto-like)
Type: Family

Delta(24)-sterol reductase, also known as Diminuto/dwarf1 homologue, catalyses the reduction of the delta-24 double bond of sterol intermediates. It exerts an anti-apoptotic function as a reactive oxygen species (ROS) scavenger .

This family also includes uncharacterised bacterial proteins.
Transcription factor CP2-like (TF_CP2-like)
Type: Family

Grainyhead/CP2 are highly conserved transcription factors in metazoa that function as key regulators of epithelial differentiation and organ development. The family comprises two distinct groups, CP2 (CCAAT box-binding protein 2) and Grh (grainyhead). All family members share a common domain architecture . Grainyhead/Elf1 was first identified in Drosophila . Three grainyhead-like (Grhl) homologues constitute the Grh subfamily in mammals . Grhl proteins are predominantly expressed in epithelial tissues and are essential regulators of epithelial development and extracellular barrier repair after tissue damage . TFCP2 (LSF, CP2 transcription factor) is a critical regulator of erythroid gene expression . It also regulates the expression of the male-dominant sex-determining gene SRY . TFCP2 can interact with NF-E4 proteins, forming a heteromeric stage selector protein complex (SSP); this complex can bind stage selector element (SSE) and regulate embryonic globin expression in fetal-erythroid cells .
Not2/Not3/Not5 (Not2/3/5)
Type: Family

The Ccr4-Not complex is a global regulator of gene expression that is conserved from yeast to human. It affects genes positively and negatively and is thought to regulate transcription factor IID function. In Saccharomyces cerevisiae, it exists in two prominent forms and consists of at least nine core subunits: the five Not proteins (Not1 to Not5), Caf1, Caf40, Caf130 and Ccr4 . The Ccr4-Not complex regulates many different cellular functions, including RNA degradation and transcription initiation. It may be a regulatory platform that senses nutrient levels and stress . Caf1 and Ccr4, are directly involved in mRNA deadenylation, and Caf1p is associated with Dhh1, a putative RNA helicase thought to be a component of the decapping complex . Pop2, a component of the Ccr4-Not complex, functions as a deadenylase .

This entry includes CCR4-NOT complex subunits Not2, Not3, Not5 and related proteins.
SURP and G-patch domain-containing protein 1/2 (SUGP1/2)
Type: Family

The function of SUGP1/2 is not clear.
Cytosolic acyl coenzyme A thioester hydrolase (Cytosol_ACT)
Type: Family

This family comprises bacterial and cytosolyc acyl-CoA thioester hydrolases. In higher organisms, acyl-CoA thioesterases (ACOTs) catalyze hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH. Different ACOT isoforms are localized to distinct cellular organelles. ACOT6 is a cytosolic isoform highly expressed in brain tissue and testis . Other cytosolic isoforms include ACOT12, which appears to be the major cytoplasmic enzyme in the liver , and ACOT11, a brown fat inducible thioesterase .
Harmonin-binding protein USHBP1-like (USBP1-like)
Type: Family

This entry includes Harmonin-binding protein USHBP1 also known as MCC2) and colorectal mutant cancer protein known as MCC.

MCC has been found to suppresses cell proliferation and the Wnt/b-catenin pathway in colorectal cancer cells . It may works as a scaffold protein regulating cell movement and able to bind Scrib, beta-catenin and NHERF1/2 . MCC1 inhibits DNA binding of b-catenin/TCF/LEF transcription factors, and it is involved in cell migration independently of RAC1, CDC42 and p21-activated kinase (PAK) activation .

MCC2 protein binds the first PDZ domain of AIE-75 with its C-terminal amino acids -DTFL. A possible role of MCC2 as a tumour suppressor has been put forward. The carboxyl terminus of the predicted protein was DTFL which matched the consensus motif X-S/T-X-phi (phi: hydrophobic amino acid residue) for binding to the PDZ domain of AIE-75 .
Renalase (RNLS)
Type: Family

Renalase is a FAD-dependent amine oxidase that catalyzes the oxidation of the less abundant 1,2-dihydro-beta-NAD(P) and 1,6-dihydro-beta-NAD(P) to form beta-NAD(P)+, activity that functions as an intracellular detoxification mechanism which alleviates inhibition of dehydrogenases by these compounds . In humans it is highly expressed in the kidneys and heart. It has been linked to chronic kidney disease and cardiovascular disease, and may serve as a potential drug target .
Methylcytosine dioxygenase TET1/2/3 (TET1/2/3)
Type: Family

The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression . TET proteins, including TET1/2/3, convert 5-methylcytosine to 5-hydroxymethylcytosine. They can also convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine . They play roles in epigenetic regulation . Human TET2 mutations have been linked to various leukaemias. TET2 and TET3 interact with O-GlcNAc transferase (OGT) and promotes OGT-mediated GlcNAcylation . The double epigenetic modifications on both DNA and histones by TET2 and OGT coordinate together for the regulation of gene transcription .
RING finger protein RNF121/RNF175 (RNF121/RNF175)
Type: Family

The family includes RNF121, RNF175 and similar proteins. RNF121 is an E3-ubiquitin ligase present in the endoplasmic reticulum (ER) and cis-Golgi compartments. It is a novel regulator of apoptosis . It also facilitates the degradation and membrane localisation of voltage-gated sodium (NaV) channels, and thus plays a role in the quality control of NaV channels during their synthesis and subsequent transport to the membrane . Moreover, RNF121 acts as a broad regulator of nuclear factor kappaB (NF-kappaB) signalling since its silencing also dampens NF-kappaB activation following stimulation of toll-like receptors (TLRs), nod-like receptors (NLRs), RIG-I-like Receptors (RLRs) or after DNA damages . RNF121 contains five conserved transmembrane (TM) domains and a C3H2C2-type RING-H2 finger. RNF175 is an uncharacterised RING finger protein that shows high sequence similarity with RNF121.
Proton-coupled zinc antiporter SLC30A9 (SLC30A9)
Type: Family

This entry includes proton-coupled zinc ion antiporters which mediate the export of zinc from the mitochondria, being involved in intracellular zinc homeostasis, zinc mobilisation as well as mitochondrial morphology and health . A mutation in the human gene leads to an autosomal recessive cerebro-renal syndrome associated with early-onset neurological deterioration, severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia . An uncharacterised homologue from Arabidopsis thaliana is known as metal tolerance protein C4 (MTPC4).
E3 ubiquitin-protein ligase RNF220, RING finger (RNF220_RING)
Type: Domain

RNF220 is an E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of Sin3B, a scaffold protein of the Sin3/HDAC (histone deacetylase) corepressor complex. It can also bind E2 and mediate auto-ubiquitination of itself. Moreover, RNF220 specifically interacts with beta-catenin, and enhances canonical Wnt signaling through ubiquitin-specific protease 7 (USP7)-mediated deubiquitination and stabilization of beta-catenin, which is independent of its E3 ligase activity . RNF220 is critical for nuclear lamina regulation and its mutations are implicated in leukodystrophy with ataxia and sensorineural deafness . RNF220 contains a characteristic C3HC4-type RING-HC finger at its C terminus .
Neuregulin (Neuregulin)
Type: Family

Neuregulins (NRG) are a sub-family of EGF-like molecules that have been shown to play multiple essential roles in vertebrate embryogenesis including: cardiac development, Schwann cell and oligodendrocyte differentiation, some aspects of neuronal development, as well as the formation of neuromuscular synapses . Included in the family are heregulin; neu differentiation factor; acetylcholine receptor synthesis stimulator; glial growth factor; and sensory and motor-neuron derived factor . Multiple family members are generated by alternate splicing or by use of several cell type-specific transcription initiation sites. In general, they bind to and activate the erbB family of receptor tyrosine kinases (erbB2 (HER2), erbB3 (HER3), and erbB4 (HER4)), functioning both as heterodimers and homodimers.
Pleckstrin homology domain-containing family G member 5/7 (PKHG5/7)
Type: Family

This entry includes pleckstrin homology domain-containing family G member 5/7 (PKHG5/7). PKHG5 is a guanine nucleotide exchange factor. PKHG5, also known as Plekhg5, has been shown to activate RHOA . Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26 . The function of PKHG7 is not clear.
Autophagy-related protein 13 (ATG13)
Type: Family

This entry represents autophagy-related protein 13 (Atg13) from yeasts, animals and plants, which functions in autophagy.

Fission yeast autophagy initiation is controlled by the Atg1 kinase complex, which is composed of the Ser/Thr kinase Atg1, the adaptor protein Atg13, and the ternary complex of Atg17-Atg31-Atg29. Atg13 recruits Atg1 to the site of autophagosome formation and enhancing Atg1 kinase activity. Atg13 may have additional functions that are independent of a direct interaction or permanent colocalization with Atg1 .
THUMP domain-containing protein 1-like (THUMPD1-like)
Type: Family

This family contains THUMP domain-only proteins including THUMP domain-containing protein 1 and Saccharomyces cerevisiae Tan1. Tan1 is non essential and has been shown to be required for the formation of the modified nucleoside N(4)-acetylcytidine (ac(4)C) in tRNA. THUMPD1 is also an adapter required for NAT10-dependent tRNA acetylation . The THUMP domain is named after thiouridine synthases, methylases and PSUSs. The domain consists of about 110 amino acid residues. It is predicted to be an RNA-binding domain and probably functions by delivering a variety of RNA modification enzymes to their targets .
Minichromosome maintenance protein 10 (Mcm10)
Type: Family

Minichromosome maintenance protein 10 (Mcm10) is a eukaryotic DNA replication factor that regulates the stability and chromatin association of DNA polymerase alpha . It is required for DNA synthesis and for entry into or completion of S phase. It is associated with the DNA polymerase-alpha (pol-alpha) primase complex throughout the cell cycle, and is a nuclear chaperone for Cdc17, which is otherwise rapidly degraded . It is also required for maintenance of transcriptional silencing .
Far11/STRP (Far11/STRP)
Type: Family

This entry includes the yeast Far11 protein and the human STRP1/2 proteins.

Budding yeast Far11 interacts with the phosphatases Pph21, Pph22, and Pph3 and may be involved in the regulation of autophagy and the DNA damage signaling . STRP1/2 (also known as FAM40A/B) are regulators of cytoskeletal organization, cell morphology and migration .
Citramalyl-CoA lyase (Citramalyl-CoA_lyase)
Type: Family

Mitochondrial citramalyl-CoA lyase converts citramalyl-CoA into acetyl-CoA and pyruvate in the C5-dicarboxylate catabolism pathway. It is indirectly involved in vitamin B12 metabolism .
OCIA domain-containing protein 1/2 (OCAD1/2)
Type: Family

This entry includes OCIA domain-containing protein 1/2 (OCAD1/2). OCAD1 is involved in integrin-mediated cancer cell adhesion and colony formation in ovarian cancer . The function of OCAD2 is not clear.
N-acetylmuramic acid 6-phosphate etherase/glucokinase regulatory protein (MURQ/GCKR)
Type: Family

N-acetylmuramic acid 6-phosphate etherase (MurQ) is an enzyme involved in peptidoglycan recycling in Escherichia coli. In cyanobacteria MurQ may promote low-light adaptation through peptidoglycan recycling . MurQ contains a sugar isomerase (SIS) domain with similarity to the glucokinase regulatory protein (GKRP) in humans .

GCKR regulates glucokinase (GK), an enzyme responsible for regulating the uptake and storage of dietary glucose . In the liver, GKRP forms an inhibitory complex with glucokinase (GCK). The disruption and reformation of this complex occurs in response to direct binding of glucose to GCK, and fructose 1-phosphate (F1P) and fructose 6-phosphate (F6P) to GKRP .
U3 small nucleolar RNA-associated protein 10 (UTP10)
Type: Family

Proteins in this entry contain an armadillo-type fold, and a BP28, C-terminal domain. It includes HEAT repeat -containing protein 1 (HEATR1) from human and its orthologues from fungi, U3 small nucleolar RNA-associated protein 10 (Utp10), which is a HEAT-repeat containing protein involved in nucleolar processing of pre-18S ribosomal RNA . Utp10 is also involved in 40S ribosome maturation . HEATR1 is a ribosome biogenesis factor required for recruitment of Myc to nucleoli . It is involved in nucleolar processing of pre-18S ribosomal RNA and it is required for optimal pre-ribosomal RNA transcription by RNA polymerase I . HEATR1 plays a role in neuronal-lineage cell proliferation .
CUE domain-containing protein 1 (CUEDC1)
Type: Family

Proteins in this family are from eukaryotes and contain a CUE domains. Human CUE domain-containing protein 1 (CUEDC1) is uncharacterised, but its tertiary structure has been solved (

).
EF-hand domain-containing protein EFHC1/EFHC2/EFHB (EFHC1/EFHC2/EFHB)
Type: Family

This entry represents a group of EF-hand domain-containing proteins, including EFHC1, EFHC2 and EFHB. EFHC1 has been shown to interact with microtubules to regulate cell division and cortical development . Mutations in the EFHC1 gene has been linked to juvenile myoclonic epilepsy . The function of EFHC2 and EFHB is not clear.
Cwf19-like protein (Cwf19-like)
Type: Family

This entry represents a group of Cwf19-like proteins, including CWF19L1/2 from humans and Drn1 from budding yeasts. Drn1 modulates turnover of branched RNAs by lariat-debranching enzyme Dbr1 .

Mutations of the CWF19L1 gene has been linked to spinocerebellar ataxia, autosomal recessive, 17 and autosomal recessive cerebellar ataxia .