SII-SWORD/CoKE huggingface dataset:
DCN1-like, PONY binding domain (DCN1-like_PONY)
Type: Homologous_superfamily

This superfamily represents a domain is found in DCN1-like proteins. Proteins of the DCN family may contribute to neddylation of cullin components of SCF-type E3 ubiquitin ligase complexes, which are multi-protein complexes required for polyubiquitination and subsequent degradation of target proteins by the 26S proteasome .

The structure of this domain is composed entirely of α helices . It has been referred to as potentiating neddylation domain (PONY) and can be found in association with an N-terminal UBA domain. The PONY domain contains a cullin-binding surface within its C-terminal region and is sufficient to promote neddylation .
LapD/MoxY periplasmic domain, C-terminal (LapD_MoxY_peri_C)
Type: Homologous_superfamily

This superfamily represents the C-terminal region found at the N-terminal periplasmic domain of the LapD and MoxY receptor proteins .
Armadillo repeat-containing protein 7 (ARMC7)
Type: Family

The function of Armadillo repeat-containing protein 7 (ARMC7) is not clear.
Haem NO binding associated domain superfamily (HNOB_dom_associated_sf)
Type: Homologous_superfamily

This superfamily represents the Haem NO binding associated domain (HNOBA). This domain occurs between the HNOB and the cyclase domains in the animal SGCs and is also detected in bacteria. The HNOB domain is predicted to function as a haem-dependent sensor for gaseous ligands, and transduce diverse downstream signals in both bacteria and animals. The HNOBA domain functionally interacts with the HNOB domain, and possibly binds a ligand, either in cooperation, or independently of the latter domain .
Xyloside xylosyltransferase 1 (XXLT1)
Type: Family

XXYLT1 (xyloside xylosyltransferase 1) is a type II membrane protein located in the endoplasmic reticulum (ER). It is a retaining glycosyltransferase (GT) that regulates the Notch receptor activation by adding xylose to the Notch extracellular domain .
Peptidase C65, otubain, subdomain 2 (Peptidase_C65_otubain_sub2)
Type: Homologous_superfamily

This superfamily represents the subdomain 2 found in the otubain (OTU-domain Ub aldehyde-binding protein) family of cysteine proteases (known as peptidase C65), involved in precise cleavage at the specific deubiquitylation at the Ub-protein bond . The OTU-domain is conserved amongst this family of proteases and is characterised by the presence of a cysteine protease motif .
Peptidase C65, otubain, subdomain 1 (Peptidase_C65_otubain_sub1)
Type: Homologous_superfamily

This superfamily represents the subdomain 1 found in the otubain (OTU-domain Ub aldehyde-binding protein) family of cysteine proteases (known as peptidase C65), involved in precise cleavage at the specific deubiquitylation at the Ub-protein bond . The OTU-domain is conserved amongst this family of proteases and is characterised by the presence of a cysteine protease motif .
E3 ubiquitin-protein ligase HECTD3 (HECTD3)
Type: Family

E3 ubiquitin-protein ligase HECTD3 is an E3 ubiquitin ligase that regulates ubiquitination and degradation of Tara , MASTL and LKB1 . HECTD3 interacts with HSP90 and is involved in the HSP90-dependent degradation of CRAF protein . It has been shown to interact and stabilize MALT1 (mucosa-associated lymphoid tissue 1), and may hence promote cell survival .
RecQ mediated genome instability protein, N-terminal OB-fold domain superfamily (RMI1_N_C_sf)
Type: Homologous_superfamily

This entry represents the N-terminal OB-fold domain of RMI (RecQ-mediated genome instability protein) proteins . This domain forms a stable complex with Bloom syndrome protein BLM and DNA topoisomerase 3-alpha .
Matrix remodeling-associated protein 8 (MXRA8)
Type: Family

Matrix remodeling-associated protein 8 (MXRA8), also known as Limitrin or DICAM, is a type I transmembrane protein with two V-type Ig domains in the extracellular region and a short cytoplasmic tail . It is involved in cell-cell adhesion through a heterophilic interaction with alphaVbeta3 integrin and acts as a negative regulator of osteoclast differentiation by suppressing the integrin alphaVbeta3 pathway . It also positively regulates primary cilia and Indian hedgehog signaling, resulting in elongation of long bone . It has been shown to be a receptor for multiple arthritogenic alphaviruses .
V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA)
Type: Family

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a type I transmembrane protein consisting of a single N-terminal immunoglobulin (Ig) V domain, an approximately 30 amino acid (aa) stalk, a transmembrane domain, and a 95 aa cytoplasmic tail . It is primarily expressed on hematopoietic cells and functions as both a ligand and a receptor . It serves as a immune-checkpoint protein that hampers the generation of effective anti-tumor immunity. Besides cancer, VISTA also regulates the development of autoimmune and inflammatory diseases .
Cell surface A33 antigen (A33)
Type: Family

A33 antigen is a cell surface glycoprotein of the small intestine and colonic epithelium with homology to tight junction-associated proteins of the immunoglobulin superfamily . It contains two extracellular immunoglobulin domains, a single transmembrane domain, and a short intracellular tail containing four acylation sites proximal to the transmembrane domain . In humans, A33 is expressed in more than 95% of colon cancers and a subset of gastric cancers. An antibody specific to A33 has been used for the development of immunotherapy .
V-set and immunoglobulin domain-containing protein 2 (VSIG2)
Type: Family

The function of V-set and immunoglobulin domain-containing protein 2 (VSIG2) is not clear.
Amyloid protein-binding protein 2 (APPBP2)
Type: Family

Amyloid protein-binding protein 2 (APPBP2), also known as PAT1, is a microtubule-interacting protein that modulates intracellular transport and processing of amyloid precursor protein (APP), APLP1, and APLP2 .
HMG domain-containing protein 4 (HMGXB4)
Type: Family

HMG domain-containing protein 4 (HMGXB4), also known as HMG2L1, is a NLK-binding protein that may play a role in early Xenopus development .
72kDa inositol polyphosphate 5-phosphatase (INPP5E)
Type: Family

INPP5E is an inositol-polyphosphate 5-phosphatase that localizes to the Golgi network . It localises to the primary cilium and may regulate PtdIns(3,4,5)P3-dependent Akt signalling . Mutations in the INPP5E gene cause Joubert syndrome 1 , mental retardation, truncal obesity, retinal dystrophy and micropenis (MORMS) .
SMC5-SMC6 complex localization factor protein 1 (Slf1)
Type: Family

The SMC5-SMC6 complex localization factor protein 1 plays a role in the DNA damage response (DDR) pathway by regulating postreplication repair of UV-damaged DNA and genomic stability maintenance . The RAD18-SLF1-SLF2 complex suppresses the genome instability by recruiting the SMC5/6 cohesion complex to DNA lesions .
Protein dispatched homolog 3 (DISP3)
Type: Family

The protein dispatched homolog 3 (DISP3) is a sterol-sensing domain-containing protein that promotes cell proliferation and alters expression of genes that are involved in tumorigenesis . It has also been shown to influence neural stem cell fate decisions .
Coiled-coil domain-containing protein 57 (CCDC57)
Type: Family

The function of Coiled-coil domain-containing protein 57 (CCDC57) is not clear.
Type VII secretion system EccB, repeat 3 domain (T7SS_EccB_R3)
Type: Homologous_superfamily

The ESX-1 type VII (T7SS) secretion system is an important determinant of virulence in pathogenic mycobacteria, including Mycobacterium tuberculosis. This complicated molecular machine secretes folded proteins through the mycobacterial cell envelope to subvert the host immune response. The protein EccB1, a core component of the T7SS, is an ATPase required for the secretion of virulence factors by the ESX-1 system. The periplasmic domain of EccB1 is composed of five domains, 4 repeat domains and a central domain. The repeat domains of EccB1 are structurally similar to a known peptidoglycan binding protein which suggest their role in anchoring the ESX-1 system within the periplasmic space .

This superfamily represents the repeat 3 (R3) domain, which flanks the core domain of EccB1.
Arabinosyltransferase, C-terminal, subdomain 2 (Arabino_trans_C_2)
Type: Homologous_superfamily

Arabinosyltransferase is involved in arabinogalactan (AG) biosynthesis pathway in mycobacteria. AG is a component of the macromolecular assembly of the mycolyl-AG-peptidoglycan complex of the cell wall. This enzyme has important clinical applications as it is believed to be the target of the antimycobacterial drug Ethambutol .

This superfamily represents the subdomain 2 of the C-terminal of arabinosyltransferase. Structurally, this domain is composed of 3 α helices and 10 β strands, arranged into a jelly-roll β sandwich.
RuvBL1/2, DNA/RNA binding domain (RuvBL1/2_DNA/RNA_bd_dom)
Type: Homologous_superfamily

RuvBL1 is a ubiquitously expressed protein that plays important roles in chromatin remodeling, transcription, DNA repair, and apoptosis. The significant evolutionary conservation of RuvBL1 from yeast to man strongly suggests that it mediates important cellular functions. RuvBL1 belongs to a large family of ATPases known as AAA proteins (ATPases associated with diverse cellular activities) which generally form hexamers. RuvBL1 is the eukaryotic homologue of the bacterial DNA-dependent ATPase and helicase RuvB .

RuvB-like helicase 2 (RUVBL2 or TIP49b;

) has single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3' to 5') activity. It forms a homohexamer which is critical for ATP hydrolysis, and forms a dodecamer with RUVBL1 . RUVBL2 is an essential cofactor for oncogenic transformation by c-Myc . It is a component of the NuA4 histone acetyltransferase , BAF53 , MLL1/MLL , INO80 and R2TP complexes.

This entry represents the second domain of RuvBL1 and RUVB2 which is involved in DNA/RNA binding .
Rad4, beta-hairpin domain 3 superfamily (Rad4_BHD3_sf)
Type: Homologous_superfamily

The xeroderma pigmentosum C (XPC) protein has a central role in initiating global-genome NER (nucleotide excision repair) by recognising the lesion and recruiting downstream factors. This entry includes the yeast XPC orthologue Rad4 bound to DNA containing a cyclobutane pyrimidine dimer (CPD) lesion. Rad4 inserts a β-hairpin through the DNA duplex, causing the two damaged base pairs to flip out of the double helix. The expelled nucleotides of the undamaged strand are recognised by Rad4, whereas the two CPD-linked nucleotides become disordered. These findings indicate that the lesions recognised by Rad4/XPC thermodynamically destabilise the Watson-Crick double helix in a manner that facilitates the flipping-out of two base pairs .

This superfamily represents the β-hairpin domain BHD3 of the Rad4 protein, which is involved in DNA binding .
F-actin capping protein, alpha subunit, domain 1 (CapZ_alpha_1)
Type: Homologous_superfamily

The F-actin capping protein binds in a calcium-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike gelsolin and severin this protein does not sever actin filaments. The F-actin capping protein is a heterodimer composed of two unrelated subunits: alpha and beta. Neither of the subunits shows sequence similarity to other filament-capping proteins .

This entry represent domain 1 found at the N terminus of the alpha subunit (CAPZA), which is a protein of about 268 to 286 amino acid residues whose sequence is well conserved in eukaryotic species . In Drosophila mutations in the alpha and beta subunits cause actin accumulation and subsequent retinal degeneration . In humans CAPZA is part of the WASH complex that controls the fission of endosomes .
Acyl-CoA thioester hydrolase/BAAT, N-terminal (Thio_Ohase/BAAT_N)
Type: Homologous_superfamily

This superfamily represents the N-terminal region of the acyl-CoA thioester hydrolase and bile acid-CoA:amino acid N-acetyltransferase (BAAT) . This region is not thought to contain the active site of either enzyme. Thioesterase isoforms have been identified in peroxisomes, cytoplasm and mitochondria, and are likely to have distinct functions in lipid metabolism . The N-terminal domain contains a seven-stranded β-sandwich, which has some distant structural homologs in other proteins .
Vacuolar protein sorting-associated protein 35, C-terminal (Vps35_C)
Type: Homologous_superfamily

This superfamily represents the α-helical C-terminal domain found in vacuolar protein sorting-associated protein 35 (Vps35) from eukaryotes.

Vps35 is a core component of the retromer complex which functions in the endosome-to-Golgi retrieval cargo transport pathway . Vps35 is part of the a cargo-selective complex trimer (CSC) of the retromer, which is composed of Vps26, Vps29 and Vps35 and is responsible for binding to and sorting protein cargo . Mutations in the Vps35 gene have been linked to Parkinson's disease . Structurally, VPS35 forms a horseshoe-shaped, right-handed, α-helical solenoid .
Bacterial type XPD DNA helicase, FeS cluster domain (XPD_DNA_FeS)
Type: Homologous_superfamily

XPD belongs to a family of ATP-dependent helicases that are characterised by a 'D-E-A-H' motif . This resembles the 'D-E-A-D-box' of other known helicases, which represents a special version of the B motif of ATP-binding proteins. In XPD, His replaces the second Asp.

XPD is divided into four domains. The first three domains together with α-helix 22 from domain 4 form a donut-shaped structure containing a hole . Domains 1 and 4 represent the RecA-like fold that is present in all helicases of superfamilies 1 and 2 (SF1 and SF2) . Domains 2 and 3 are insertions, which emerge from domain 1. Domain 2 displays an exclusively α-helical architecture consisting of six α-helices and one 3-10 helix that surround the central 4Fe4S cluster. The FeS cluster is coordinated by four cysteines, consistent with the coordination typically observed in 4Fe4S clusters . The FeS domain is vital for its helicase activity and might be involved in the damage recognition process .

This entry represents the FeS cluster domain found in XPD family members that are mostly from bacteria and archaea.
E3 ubiquitin-protein ligase RNF103 (RNF103)
Type: Family

RNF103, also known as Kf-1, is an ER ubiquitin ligase involved in the ERAD pathway . Mice lacking the kf-1 gene have been shown to exhibit increased anxiety .
Platelet-derived growth factor receptor-like protein (PDGFRL)
Type: Family

The function of the platelet-derived growth factor receptor-like protein (PDGFRL) is not clear.
Cell growth regulator with RING finger domain protein 1 (CGRF1)
Type: Family

The Cell growth regulator with RING finger domain protein 1 (CGRF1), also known as CGR19, is a ring-finger domain containing protein that has been shown to inhibit the growth of several cell lines .
Rubella membrane glycoprotein E1, domain 2 (Rubella_E1_2)
Type: Homologous_superfamily

Rubella virus (RV), the sole member of the genus Rubivirus within the family Togaviridae, is a small enveloped, positive strand RNA virus. The nucleocapsid consists of 40S genomic RNA and a single species of capsid protein which is enveloped within a host-derived lipid bilayer containing two viral glycoproteins, E1 (58kDa) and E2 (42-46kDa). In virus infected cells, RV matures by budding either at the plasma membrane, or at the internal membranes depending on the cell type and enters adjacent uninfected cells by a membrane fusion process in the endosome, directed by E1-E2 heterodimers. The heterodimer formation is crucial for E1 transport out of the endoplasmic reticulum to the Golgi and plasma membrane. In RV E1, a cysteine at position 82 is crucial for the E1-E2 heterodimer formation and cell surface expression of the two proteins. E1 has been shown to be a type 1 membrane protein, rich in cysteine residues with extensive intramolecular disulphide bonds .

This superfamily represents the domain 2 found in Rubella membrane glycoprotein E1. Structurally, it consists of 6 β strands and 2 α helices.
Rubella membrane glycoprotein E1, domain 3 (Rubella_E1_3)
Type: Homologous_superfamily

Rubella virus (RV), the sole member of the genus Rubivirus within the family Togaviridae, is a small enveloped, positive strand RNA virus. The nucleocapsid consists of 40S genomic RNA and a single species of capsid protein which is enveloped within a host-derived lipid bilayer containing two viral glycoproteins, E1 (58kDa) and E2 (42-46kDa). In virus infected cells, RV matures by budding either at the plasma membrane, or at the internal membranes depending on the cell type and enters adjacent uninfected cells by a membrane fusion process in the endosome, directed by E1-E2 heterodimers. The heterodimer formation is crucial for E1 transport out of the endoplasmic reticulum to the Golgi and plasma membrane. In RV E1, a cysteine at position 82 is crucial for the E1-E2 heterodimer formation and cell surface expression of the two proteins. E1 has been shown to be a type 1 membrane protein, rich in cysteine residues with extensive intramolecular disulphide bonds .

This superfamily makes up the membrane-distal domain 3 found in rubella membrane glycoprotein E1. Structurally, it consists of 9 β strands and 1 α helix.
Rubella membrane glycoprotein E1, domain 1 (Rubella_E1_1)
Type: Homologous_superfamily

Rubella virus (RV), the sole member of the genus Rubivirus within the family Togaviridae, is a small enveloped, positive strand RNA virus. The nucleocapsid consists of 40S genomic RNA and a single species of capsid protein which is enveloped within a host-derived lipid bilayer containing two viral glycoproteins, E1 (58kDa) and E2 (42-46kDa). In virus infected cells, RV matures by budding either at the plasma membrane, or at the internal membranes depending on the cell type and enters adjacent uninfected cells by a membrane fusion process in the endosome, directed by E1-E2 heterodimers. The heterodimer formation is crucial for E1 transport out of the endoplasmic reticulum to the Golgi and plasma membrane. In RV E1, a cysteine at position 82 is crucial for the E1-E2 heterodimer formation and cell surface expression of the two proteins. E1 has been shown to be a type 1 membrane protein, rich in cysteine residues with extensive intramolecular disulphide bonds .

This superfamily represents the domain 1 found in tubella membrane glycoprotein E1. Structurally, it consists of 8 β sheets which are not contributed by a contiguous polypeptide chain.
MukB, hinge domain superfamily (MukB_hinge_sf)
Type: Homologous_superfamily

This superfamily represents the hinge domain of E. coli's chromosome partition protein MukB, homologous to the SMC (structural maintenance of chromosomes) protein found in eubacteria. MukB and topo IV interact physically. MukB can stimulate the ability of topo IV to relax negatively supercoiled DNA. This hinge domain, also known as dimerisation domain, is not only involved in dimerisation, but it has also been implicated in both conformational flexibility and dynamic protein-DNA interactions .
Transmembrane 7 superfamily member 3 (TM7SF3)
Type: Family

TM7SF3 is a seven transmembrane orphan receptor which inhibits cytokine-induced death of pancreatic beta cells . It also maintains protein homeostasis and promotes cell survival through attenuation of ER stress. Interestingly, p53 promotes the expression of TM7SF3 that acts to restrict p53 activity .
E2 regulatory, transactivation domain, subdomain 1 (Regulatory_protein_E2_N_1)
Type: Homologous_superfamily

E2 is an early regulatory protein found in the dsDNA papillomaviruses. E2 regulates viral transcription and DNA replication. It binds to the E2RE response element (5'-ACCNNNNNNGGT-3') present in multiple copies in the regulatory region. It can either activate or repress transcription, depending on E2RE's position with regard to proximal promoter elements. Repression occurs by sterically hindering the assembly of the transcription initiation complex. The E1-E2 dimer complex binds to the origin of DNA replication .

This superfamily represents the first of two subdomains within the N-terminal or transactivation domain of E2. Structurally, this domain consists of 3 α helices in a helical hairpin structure.
E2 regulatory, transactivation domain, subdomain 2 (Regulatory_protein_E2_N_2)
Type: Homologous_superfamily

E2 is an early regulatory protein found in the dsDNA papillomaviruses. E2 regulates viral transcription and DNA replication. It binds to the E2RE response element (5'-ACCNNNNNNGGT-3') present in multiple copies in the regulatory region. It can either activate or repress transcription, depending on E2RE's position with regard to proximal promoter elements. Repression occurs by sterically hindering the assembly of the transcription initiation complex. The E1-E2 dimer complex binds to the origin of DNA replication .

This superfamily represents the second of two subdomains within the N-terminal or transactivation domain of E2.
Cytoplasmic dynein 2 intermediate chain 1 (DYNC2I1)
Type: Family

DYNC2I1 (also known as WDR60) is part of the dynein-2 complex, which drives retrograde ciliary protein trafficking by associating with the intraflagellar transport (IFT) machinery . It plays a major role in the dynein-2 complex to mediate retrograde ciliary protein trafficking in cilia and flagella . Mutations in the WDR60 gene cause Jeune asphyxiating thoracic dystrophy (JATD) and short-rib polydactyly syndrome (SRPS) .
IQ domain-containing protein C (IQCC)
Type: Family

The function of IQ domain-containing protein C (IQCC) is not clear.
TBC1 domain family member 19 (TBC1D19)
Type: Family

TBC1 domain family member 19 (TBC1D19) contains the Tre-2/Bub2/Cdc16 (TBC) domain, a conserved protein motif that consists of approximately 200 amino acids and is thought to function as a specific Rab-GAP domain .
F-box/WD repeat-containing protein 5 (FBXW5)
Type: Family

FBXW5 is a F-box protein and a DDB1-binding WD40 (DWD) protein that serves as a substrate recognition component of both SCF (SKP1-CUL1-F-box protein) and DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes . It has also been shown to negatively regulate TAK1 MAP3K in the IL-1beta signaling pathway . Interestingly, FBXW5 binds centriolar protein HsSAS-6 and promotes its ubiquitylation; this way FBXW5 can restrict centrosome re-duplication through degradation of HsSAS-6 .
Zinc finger CCHC domain-containing protein 3 (ZCCHC3)
Type: Family

Zinc finger CCHC domain-containing protein 3 from humans (ZCCHC3) is a zinc-finger protein that acts as a co-sensor of cGAS in innate immune response to cytosolic dsDNA and DNA virus . It has been shown to bind DNA and RNA in the cytoplasm and acts by promoting recognition of viral nucleic acids by virus sensors, such as DDX58/RIG-I, IFIH1/MDA5 and CGAS . Members of this family are found in eukaryotes.
Protein CIP2A (CIP2A)
Type: Family

Cancerous inhibitor of PP2A (CIP2A) functions via protein binding through interactions with many other proteins including MYC, polo like kinase (PLK1) and NIMA protein. It is an inhibitor of PP2A, a tumour suppressor. CIP2A binds to PP2A and inhibits its phosphatase functions resulting in tumorigenic transformation of cells . CIP2A is overexpressed at a high frequency in a number of tumours and expression levels are independent markers for long-term outcomes in many of these tumours .
DNA replication regulator Sld3 (Sld3)
Type: Family

Sld3 interacts with Cdc45 and plays a role in chromosomal DNA replication .
TLC domain-containing protein 5 (TLCD5)
Type: Family

The function of TLCD5 is not clear.