SII-SWORD/CoKE huggingface dataset:
Sterol transport protein NPC2-like (NPC2-like)
Type: Family

Proteins in this family contain an MD-2-related lipid-recognition (ML) domain, which is implicated in lipid recognition, particularly in the recognition of pathogen related products. It has an immunoglobulin-like β-sandwich fold similar to that of E-set Ig domains. This domain is present in proteins from plants, animals and fungi, including the following proteins:

NPC intracellular cholesterol transporter 2 (NPC2), which is known to bind cholesterol. Niemann-Pick disease type C2 is a fatal hereditary disease characterised by accumulation of low-density lipoprotein-derived cholesterol in lysosomes .

Phosphatidylglycerol/phosphatidylinositol transfer protein (Npc2) from yeasts, which catalyses the intermembrane transfer of phosphatidylglycerol and phosphatidylinositol .

House-dust mite allergen proteins such as Der f 2 from Dermatophagoides farinae and Der p 2 from Dermatophagoides pteronyssinus .
Protein THEMIS (THEMIS)
Type: Family

This entry includes THEMIS1/2/3 from animals. THEMIS1 and THEMIS2 are restricted to B and myeloid cells, and the more distantly related THEMIS3 is expressed in the large and small intestine. THEMIS is involved in the early TCR (T-cell antigen receptor) signal transduction and thymocyte selection . It is recruited to LAT through GRB2 association and LAT phosphotyrosine GRB2 binding sites . THEMIS contains CABIT modules that bind directly to the SHP-1 PTP (protein tyrosine phosphatase) domain and inhibit SHP-1 PTP activity by promoting or stabilizing oxidation of the catalytic cysteine .
Lactose permease-like (MFS_2)
Type: Family

This family includes lactose permease (LacY) and its homologues that are members of the sodium:galactoside symporter (TC 2.A.2) family. LacY is found in Firmicute bacteria such as
Streptococcus thermophilus
, and is required for transport of beta-galactosides into the cell. Cations are co-transported. LacY contains a PTS EIIA type-1 domain, which may be regulatory. It is an integral membrane protein with many transmembrane regions . Other homologues in this family include the melibiose carrier protein (MelB) from
Escherichia coli
, which is required for the transport of melibiose and other galactosides ; glucuronide carrier protein (UidB or GusB), also from
E. coli
, which transports glucuronide (but is inactive in some strains) ; and isoprimeverose transporter (XylP) from
Lactobacillus pentosus
, which transports isoprimeverose . A human member of this family, MFSD12, has been recently characterised as a transporter that mediates the import of cysteine into melanosomes, thereby regulating skin pigmentation . In melanosomes, cysteine import is required both for normal levels of cystine, the oxidized dimer of cysteine, and provide cysteine for the production of the cysteinyldopas used in pheomelanin synthesis, thereby regulating skin pigmentation . In non-pigmented cells, it catalyses the import of cysteine into lysosomes .
DNA-binding protein SATB1/SATB2 (SATB1/SATB2)
Type: Family

This entry includes SATB1/2 from animals. SATB1 is a global gene regulator that acts as a "docking site" for several chromatin remodeling enzymes and recruits corepressors (HDACs) or coactivators (HATs) directly to promoters . SATB1 can bind DNA specifically to the consensus SATB1-binding sequence (CSBS) consisting of two 5'-TAATA-3' half-sites that are arranged as inverted repeats flanking a central cytosine or guanine. It can also bind DNA non-specifically . SATB1 has been shown to bind to the nuclear matrix attachment regions (MARs) of the immunoglobulin heavy chain intronic enhancer , while SATB2 has been shown to bind to the MARs of the endogenous immunoglobulin micro locus in pre-B cells and enhances gene expression .

SATB1 is an identified oncogene, its increased expression is associated with poor prognosis in many cancers . Mutations in the SATB2 gene cause SATB2-associated syndrome (SAS), characterised by developmental delay/intellectual disability with absent or limited speech development, craniofacial abnormalities, behavioral problems, dysmorphic features, and palatal and dental abnormalities .
CASP8-associated protein 2 (FLASH)
Type: Family

CASP8-associated protein 2 (CASP8AP2), also known as FLASH, is involved in various cellular functions, such as cell cycle progression, transcriptional regulation, the regulation of apoptosis, and the regulation of histone gene expression . It is an essential component of Cajal bodies and is involved in the apoptosis receptor signaling pathway .

FLASH contains the N terminus required for histone pre-mRNA processing, the C-terminal segment which forms a SANT/Myb-like domain, and a small central region which binds Ars2 essential for cell cycle progression . Its N-terminal domain has been found to form a 2:1 heterotrimer with Lsm11 for histone pre-mRNA 3'-end processing .
Cartilage intermediate layer protein 1/2 (CILP1/CILP2)
Type: Family

This entry includes cartilage intermediate layer proteins 1 (CILP1) and 2 (CILP2). CILP1 acts as a modulator of lumbar disc disease susceptibility . CILP1 interferes with pro-fibrotic TGFbeta signalling and is a mediator of cardiac extracellular matrix remodeling . CILP2 is present in human articular cartilage and may be associated with collagen VI containing suprastructures .
Acyloxyacyl hydrolase (AOAH)
Type: Family

Acyloxyacyl hydrolase (AOAH) is a a host enzyme that removes the secondary (acyloxyacyl-linked) fatty acids from LPS (a potent bacterial endotoxin), rendering it immunologically inert . This activity is important for the recovery from immune tolerance that follows Gram-negative infection .
Ciliogenesis and planar polarity effector 2 (RSG1)
Type: Family

Ciliogenesis and planar polarity effector 2, also known as RSG1, is a small GTPase that controls a final step in primary cilia initiation . It interacts with FUZZY (FUZ), which is part of the CPLANE (ciliogenesis and planar polarity effector) protein complex .
Beta-catenin-like protein 1 (CTNNBL1)
Type: Family

This entry includes beta-catenin-like protein 1 (CTNNBL1) and related proteins from animals, fungi and plants. Mammalian CTNNBL1is an AID (activation-induced cytidine deaminase)-interacting factor that is required for immunoglobulin class switch recombination .
Nuclear receptor-binding factor 2 (NRBF2)
Type: Family

Nuclear receptor-binding factor 2 (NRBF2) plays an essential role in autophagy, the cellular pathway that degrades long-lived proteins and other cytoplasmic contents through lysosomes. NRBF2 binds Atg14L - a Beclin-binding protein - directly via the MIT domain and enhances Atg14L-linked Vps34 kinase (a class III phosphatidylinositol-3 kinase) activity and autophagy induction .
Pleckstrin homology domain-containing family B member 1/2 (PLEKHB1/2)
Type: Family

This entry includes pleckstrin homology domain-containing family B (PLEKHB) members 1 and 2 (also known as evectins 1 and 2). They are vesicular proteins. Evectin1 (evt-1) has been found to localize to rhodopsin-bearing membranes of the post-Golgi in photoreceptors . Evectin2 is a recycling endosomal protein that can specifically bind phosphatidylserine through its PH domain .
Interleukin-18-binding protein (IL18BP)
Type: Family

Interleukin-18-binding protein (IL18BP) isoform A binds to IL-18 and inhibits its activity . It is required for normal NK cell abundance and function and also contributes to maintaining steady-state levels of circulating IL-18 .
Exocyst complex component Sec8/EXOC4 (Sec8/EXOC4)
Type: Family

This entry includes Sec8 from fungi and EXOC4 from animals. Sec8 is a component of the exocyst complex essential for targeting exocytic vesicles to specific docking sites on the plasma membrane . In fission yeasts, the exocyst complex is also required for polarized cell growth and division septum assembly . EXOC4 has been shown to regulate N-cadherin expression by controlling Smad3 and Smad4 expression through CREB binding protein, thereby mediating the epithelial-mesenchymal transition and early embryonic development .
Protein Lsm12-like (Lsm12-like)
Type: Family

This entry represents Lsm12 and its homologues. Lsm12 is a putative RNA-binding and regulation protein that might be involved in mRNA degradation or tRNA splicing . Recently, it was demonstrated that it binds nicotinic acid adenine dinucleotide phosphate (NAADP) that confers NAADP sensitivity to the two pore channel complex (TPCs) by acting as TPC accessory protein necessary for NAADP-evoked Ca2 release . Therefore, further studies of the potential crosstalk between NAADP signaling and RNA regulation are required.

Sm and Sm-like proteins of the Lsm (like Sm) domain family are generally involved in essential RNA-processing tasks . All the LSM proteins are evolutionarily conserved in eukaryotes with an N-terminal Lsm domain to bind nucleic acids followed by a C-terminal region, some of which have a C-terminal methyltransferase domain.
Fanconi anemia group G protein (FANCG)
Type: Family

Fanconi anemia (FA) is a human disorder characterised by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. This entry represents FANCG, which is part of the FA core complex required for the monoubiquitylation of FANCD2 and the FANCI heterodimer. The FA complex coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination . Besides being part of the FA complex, FANCG also promotes formation of a protein complex containing BRCA2, FANCD2 and XRCC3 .
Fanconi anemia group E protein (FANCE)
Type: Family

Fanconi anemia (FA) is a human disorder characterised by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. The FA complex repairs the interstrand cross-linking (ICL) lesions and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. It is required for the monoubiquitylation of FANCD2 and FANCI heterodimer. The FA core complex consists of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, FANCT (UBET2), FAAP100 and FAAP24 .

The FA group E protein (FANCE) has an important role in DNA repair, functioning as the FANCD2-binding protein in the FA core complex .
FANCM/Mph1-like, insert domain (FANCM/Mph1-like_ID)
Type: Domain

This entry includes a group of evolutionarily conserved ATP-dependent DNA helicases/translocases including human FANCM (Fanconi anemia group M protein) and its homologues, such as Mph1 from S. cerevisiae and Fml1/2 from S. pombe.

FANCM is part of the FA complex that repair the interstrand cross-linking (ICL) lesions and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination . It also plays a critical role in the replication stress response .

Mph1 can unwind Rad51 D-loops and extended D-loops . It has been shown to be regulated by the Smc5/6 complex .

This entry represents the insert domain (ID) of FANCM and related proteins. This domain, which shows an α-helical structure, is located in the N-terminal SF2 helicase domain, which contains three parts.
Nephrocystin-1 (NPHP1)
Type: Family

Nephronophthisis (NPHP) is a hereditary cystic kidney disorder that causes renal failure in children and young adults and can be associated with various extrarenal disorders, including retinitis pigmentosa. Six NPHP genes have been identified, one of which, Nephrocystin-1 (NPHP1), is localised to the ciliary transition zone of epithelial cells or its analogous structure, connecting cilia of retinal photoreceptors . It also plays an essential role in photoreceptor intraflagellar transport and in later steps of sperm morphogenesis in mice .

This entry also includes C. elegans NPHP1, which may act as a sensory transducer .
STAC1/2/3 (STAC1/2/3)
Type: Family

Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C terminus. There are three mammalian members: Stac1, Stac2, and Stac3. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C terminus. They regulate voltage-gated calcium channel (CaV) trafficking and function .
B-cell differentiation antigen CD72 (CD72)
Type: Family

This entry includes CD72 from mammals and similar proteins from vertebrates. Human CD72 is a membrane protein expressed mostly in B cells. It contains a C-type lectin-like domain (CTLD) in the extracellular region and an immunoreceptor tyrosine-based inhibition motif (ITIM) in the cytoplasmic region. It is involved in B-cell proliferation and differentiation . It plays a role in regulation of the development of systemic lupus erythematosus (SLE), an autoimmune disease characterised by production of autoantibodies to various nuclear components and inflammatory lesions caused by deposition of immune complexes .
U11/U12 small nuclear ribonucleoprotein 25kDa protein (SNRNP25)
Type: Family

U11 and U12 small nuclear ribonucleoprotein (snRNPs) bind U12-type pre-mRNAs as a preformed di-snRNP complex, simultaneously recognizing the 5' splice site and branchpoint sequence. SNRNP25 is a component of the U11/U12 snRNP complex . Homologues are known from animals, plants and fungi.
Zinc finger CCCH domain-containing protein A/B (ZC3H7A/B)
Type: Family

Zinc finger CCCH domain-containing proteins A (ZC3H7A) and B (ZC3H7B) bind to microRNAs MIR7-1, MIR16-2 and MIR29A hairpins recognizing the 3'-ATA(A/T)-5' motif in the apical loop . Homologues are known from animals.
Rtr1/RPAP2 (Rtr1/RPAP2)
Type: Family

This entry includes Rtr1 from budding yeasts and its homologues, including RPAP2 from humans. Homologues are known from animals, plants and fungi. Rtr1 and Rtr2 are paralogues. Rtr1 is a RNA polymerase II (RNAPII)-binding protein. It is responsible for the transition of PolII into the elongation and termination phases of transcription by removing RNAPII CTD serine 5 phosphorylation (Ser5-P) at a selection of target genes .

Human RPAP2 is a CTD phosphatase that interacts directly with the RNA polymerase II subunit Rpb6 and participates in pre-mRNA 3'-end formation .
WD repeat-containing protein 11 (WDR11)
Type: Family

Members of the WDR11 family share a domain architecture consisting of two β-propellers followed by a TPR domain. WDR11 has been implicated in human developmental genetic disorders characterised by delayed puberty and infertility. WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for adequate ciliogenesis . The β-propellers in WDR11 are involved in protein-protein interaction. This are essential for proper interaction with EMX1, a homeodomain transcription factor involved in the development of olfactory neurons. Impaired pubertal development is suggested to result from a deficiency of productive WDR11 protein interaction . WDR11 is also involved in vesicle traffic as it binds TBC1D23, a vesicle-golgin adaptor required for endosome-to-Golgi trafficking . WDR11 is part of the WDR11 complex (consisting of WDR11, C17orf75 and FAM91A) that facilitates the tethering of AP-1-derived vesicles . Mutations of the WDR11 gene have been linked to congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility .
Polyprenal reductase (Dfg10/SRD5A3)
Type: Family

This entry represents a group of polyprenal reductases, including SRD5A3 from humans, PPRD1 from Arabidopsis and Dfg10 from budding yeasts. SRD5A3 was initially characterised as a polyprenol reductase, mediating the conversion of polyprenol into dolichol . However, it was later shown to catalyse an intermediate step in this pathway and reduce polyprenal . Mutations in the SRD5A3 gene cause congenital disorder of glycosylation 1Q, a genetic disease with an extremely broad spectrum of clinical presentations due to defective glycosylation of glycoproteins and glycolipids . PPRD2 deficiency results in aberrant development of the male gametophyte and sporophyte . Homologues are known from animals, plants and fungi.
Large ribosomal subunit protein uL30 (Ribosomal_uL30)
Type: Family

This entry includes the the large ribosomal subunit protein uL30 from eukaryotes and archaea (which are also known as L7 subunit) and the ribosome biogenesis protein RLP7 (ribosomal protein L7-like) from yeasts. RLP7 is required for the biogenesis of the 60S ribosomal subunit .

Ribosomal protein uL30 is one of the proteins from the large ribosomal subunit. uL30 belongs to a family of ribosomal proteins which, on the basis of sequence similarities , groups bacteria and archaea L30, yeast mitochondrial L33, and Drosophila melanogaster, Dictyostelium discoideum (Slime mold), fungal and mammalian uL7 ribosomal proteins. uL30 from bacteria are small proteins of about 60 residues, those from archaea are proteins of about 150 residues, and eukaryotic L7 are proteins of about 250 to 270 residues.
Lymphocyte antigen 6G6e (Ly6g6e)
Type: Family

Lymphocyte antigen 6G6e (Ly6g6e) may act as a modulator of nicotinic acetylcholine receptor (nAChR) activity . Homologues are known from mammals.
HCLS1-binding protein 3 (HS1BP3)
Type: Family

Hematopoietic lineage cell-specific protein-1 (HS1) binding protein 3 (HS1BP3) associates with HS1 proteins through their SH3 domains, suggesting a role in mediating signaling. It has been reported that HS1BP3 might affect the IL-2 signaling pathway in hematopoietic lineage cells . Mutations in HS1BP3 may also be associated with familial Parkinson disease and essential tremor .
Farnesyl pyrophosphate synthase-like (FPS1-like)
Type: Family

Farnesyl pyrophosphate synthase (FPS;

; also known as Erg2) and geranylgeranyl diphosphate synthase (GGPS) are key enzymes in the synthesis of various isoprenoid-containing compounds and proteins. FPS catalyzes the sequential condensation of isopentenyl pyrophosphate to form farnesyl pyrophosphate. FPS is a Mg
2
-containing protein, binding three ions . In Schizosaccharomyces pombe, GGPS is a paralogue of FPS, and geranylgeranyl diphosphate synthase is a heterodimer of FPS and GGPS .

This family also includes a further isoprenoid biosynthesis enzyme, chrysanthemyl diphosphate synthase (also known as bifunctional chrysanthemol synthase, chloroplastic) from plants, which has been shown to catalyse two pathway steps in the biosynthesis of pyrethrins .
Protein N-terminal amidase (Nta1)
Type: Family

Nta1 is an amidase that removes the amide group from N-terminal asparagine and glutamine residues to generate proteins with N-terminal aspartate and glutamate residues that are targets of ubiquitin-mediated degradation .
Myogenic factor (Myogenic_factor)
Type: Family

Myogenic factors are involved in muscle differentiation, inducing fibroblasts to differentiate into myoblasts. Myogenic factor 5 (Myf5) is responsible for directing cells to the skeletal myocyte lineage during development . Myf5 and Myod (myoblast determination protein 1) are predominantly expressed in proliferating myoblasts while Myf4 and Myf6 are involved in differentiation of myotubes . Myogenin (MYOG) is a transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle differentiation, cell cycle exit and muscle atrophy .
Major intrinsically disordered Notch2-binding receptor 1-like (MINAR1-like)
Type: Family

Major intrinsically disordered Notch2-binding receptor 1 (MINAR1) is a Notch2-binding protein that has been shown to inhibit angiogenesis and breast cancer growth. MINAR1 is a single-pass type I membrane protein . Homologues are found in vertebrates.
Macrophage-expressed gene 1 protein (MPEG1)
Type: Family

The function of macrophage-expressed gene 1 protein (MPEG1) is not known. MPEG1 is a single-pass type I membrane protein; it is expressed in macrophages and peripheral blood monocytes .
Probable membrane protein MT1774/Rv1733c-like (MT1774/Rv1733c-like)
Type: Family

This entry represents a group of bacterial proteins, including MT1774 and Rv1733c from Mycobacterium tuberculosis. Their function is not known. Homologues are known only from Actinobacteria.
Putative antitoxin VapB3-like (VapB3-like)
Type: Family

This entry represents a group of archaeal proteins, including VapB3 from Pyrobaculum aerophilum. VapB3 (also known as PAE0152) is a putative antitoxin .
Protein GDF5OS, mitochondrial (GDF5OS)
Type: Family

The function of mitochondrial protein GDF5OS, also known as GDF5 antisense RNA 1 (GDF5-AS1), is not known. Orthologues are known only from mammals.
Meiotic expression up-regulated protein 6 (Meu6)
Type: Family

The function of meiotic expression up-regulated protein 6 (Meu6) is not known. meu6 contains a PH (pleckstrin homology) domain. Homologues are known from fungi.
At2g23090-like (At2g23090-like)
Type: Family

This uncharacterised family contains proteins from fungi and plants, including At2g23090 from Arabidopsis.
Transmembrane protein 134 (TMEM134)
Type: Family

The function of transmembrane protein 134 (TMEM134) is not known. It has been shown to interact with E virus ORF2 .
Zinc finger CCHC domain-containing protein 10 (ZCCHC10)
Type: Family

The function of zinc finger CCHC domain-containing protein 10 (ZCCHC10) is not known.
Protein Hgh1 (Hgh1)
Type: Family

The function of Hgh1 is not known.
Ribonucleoside-diphosphate reductase large subunit (Rrm1)
Type: Family

Ribonucleotide reductase (RNR,

) catalyses the reductive synthesis of deoxyribonucleotides from their corresponding ribonucleotides. It provides the precursors necessary for DNA synthesis. RNRs divide into three classes on the basis of their metallocofactor usage. Class I RNRs, found in eukaryotes, bacteria, bacteriophage and viruses, use a diiron-tyrosyl radical, Class II RNRs, found in bacteria, bacteriophage, algae and archaea, use coenzyme B12 (adenosylcobalamin, AdoCbl). Class III RNRs, found in anaerobic bacteria and bacteriophage, use an FeS cluster and S-adenosylmethionine to generate a glycyl radical. Many organisms have more than one class of RNR present in their genomes.

Ribonucleotide reductase is an oligomeric enzyme composed of a large subunit (700 to 1000 residues) and a small subunit (300 to 400 residues) - class II RNRs are less complex, using the small molecule B12 in place of the small chain .

The reduction of ribonucleotides to deoxyribonucleotides involves the transfer of free radicals, the function of each metallocofactor is to generate an active site thiyl radical. This thiyl radical then initiates the nucleotide reduction process by hydrogen atom abstraction from the ribonucleotide . The radical-based reaction involves five cysteines: two of these are located at adjacent anti-parallel strands in a new type of ten-stranded α/β-barrel; two others reside at the carboxyl end in a flexible arm; and the fifth, in a loop in the centre of the barrel, is positioned to initiate the radical reaction . There are several regions of similarity in the sequence of the large chain of prokaryotes, eukaryotes and viruses spread across 3 domains: an N-terminal domain common to the mammalian and bacterial enzymes; a C-terminal domain common to the mammalian and viral ribonucleotide reductases; and a central domain common to all three .
F-box only protein 28 (FBXO28)
Type: Family

F-box only protein 28 (FBXO28) is required for proper mitotic progression. It may regulate topoisomerase IIalpha decatenation activity and plays an important role in maintaining genomic stability .
Transmembrane protein 94 (TMEM94)
Type: Family

This entry includes Transmembrane protein 94 (TMEM94), also known as endoplasmic reticulum magnesium-transporting P-type ATPase ERMA., a protein that could function in the uptake of Mg2 from the cytosol into the endoplasmic reticulum and regulate intracellular Mg2 homeostasis . TMEM94 deletion in mice is embryonically lethal, and TMEM94 mutations in humans are associated with multi-organ functional defects revealing its essential function . TMEM94 has been proposed as a major molecular component of ERMg2+ uptake machinery in eukaryotes and its absence could lead to perturbation of signal transduction and detrimental physiological outcomes .