SII-SWORD/CoKE huggingface dataset:
TFIIS/LEDGF domain superfamily (TFIIS/LEDGF_dom_sf)
Type: Homologous_superfamily

This superfamily is composed of the Transcription factor IIS (TFIIS) and the Lens epithelium-derived growth factor (LEDGF) domains.

Transcription factor IIS (TFIIS) is a transcription elongation factor that increases the overall transcription rate of RNA polymerase II by reactivating transcription elongation complexes that have arrested transcription. The three structural domains of TFIIS are conserved from yeast to human. The 80 or so N-terminal residues form a protein interaction domain containing a conserved motif, which has been called the LW motif because of the invariant leucine and tryptophan residues it contains. This N-terminal domain is not required for transcriptional activity, and while a similar sequence has been identified in other transcription factors, and proteins that are predominantly nuclear localized , the domain is also found in proteins not directly involved in transcription. This domain is found in (amongst others):

MED26 (also known as CRSP70 and ARC70), a subunit of the Mediator complex, which is required for the activity of the enhancer-binding protein Sp1.

Elongin A, a subunit of a transcription elongation factor previously known as SIII. It increases the rate of transcription by suppressing transient pausing of the elongation complex.

PPP1R10, a nuclear regulatory subunit of protein phosphatase 1 that was previously known as p99, FB19 or PNUTS.

IWS1, which is thought to function in both transcription initiation and elongation.

The TFIIS N-terminal domain is a compact four-helix bundle. The hydrophobic core residues of helices 2, 3, and 4 are well conserved among TFIIS domains, although helix 1 is less conserved .

Lens epithelium-derived growth factor (LEDGF), also known as transcriptional co-activator p75, is a chromatin-associated protein that protects cells from stress-induced apoptosis. It is the binding partner of HIV-1 integrase in human cells . The integrase binding domain (IBD) of LEDGF is a compact right-handed bundle composed of five α-helices. The residues essential for the interaction with the integrase are present in the inter-helical loop regions of the bundle structure. The integrase binding domain is not unique to LEDGF, as a second human protein, hepatoma-derived growth factor-related protein 2 (HRP2), contains a homologous sequence .
Herpesvirus protease superfamily (Herpes_virus_sf)
Type: Homologous_superfamily

Herpesvirus protease is required for the life cycle of the virus and is an attractive target for the design and development of new anti-herpes agents. The protease belongs to a new class of serine proteases, with a novel backbone fold and a unique Ser-His-His catalytic triad .
Fibroblast growth factor 15/19/21 (FGF15/19/21)
Type: Family

This entry includes fibroblast growth factor 15/19/21 (FGF15/19/21).

Fibroblast growth factor 15 (FGF15) plays a key role in enterohepatic signaling, regulation of liver bile acid biosynthesis, gallbladder motility and metabolic homeostasis . Mouse FGF15 has been shown to be stimulated when bile acids bind to farnesoid X receptor (FXR) , and is therefore thought to a factor in chronic bile acid diarrhoea and in certain metabolic disorders .

FGF15 has been experimentally characterised in mouse, but has not been found in other species. However, there is an orthologous human protein, FGF19, and together they share about 50% amino acid identity and display similar endocrine functions, so are often referred to as FGF15/19 . FGF15 and FGF19 differ from other FGFs due to subtle changes in their tertiary structure, they have low heparin binding affinity enabling them to diffuse away from their site of secretion and signal to distant cells. FGF signaling through the FGF receptors is also different, as they require klotho protein cofactors rather than heparin sulfate proteoglycan .

Fibroblast growth factor 19 (FGF19) plays a key role in enterohepatic signaling, regulation of liver bile acid biosynthesis, gallbladder motility and metabolic homeostasis . Human FGF19 expression has been shown to be stimulated approximately 300-fold by physiological concentrations of bile acids including chenodeoxycholic acid, glycochenodeoxycholic acid and obeticholic acid in explants of ileal mucosa . The protein is thought to be a factor in chronic bile acid diarrhoea and in certain metabolic disorders .

FGF21 stimulates glucose uptake in differentiated adipocytes via the induction of glucose transporter SLC2A1/GLUT1 expression . FGF21 has been shown to protect animals from diet-induced obesity when overexpressed in transgenic mice. It also lowers blood glucose and triglyceride levels when administered to diabetic rodents , suggesting it may exhibit the therapeutic characteristics necessary for effective treatment of diabetes. Treatment of animals with FGF21 results in increased energy expenditure, fat utilisation and lipid excretion . FGF21 is most abundantly expressed in the liver, and also expressed in the thymus at lower levels .
GYF-like domain superfamily (GYF-like_dom_sf)
Type: Homologous_superfamily

The glycine-tyrosine-phenylalanine (GYF) domain is an around 60-amino acid domain which contains a conserved GP[YF]xxxx[MV]xxWxxx[GN]YF motif. It was identified in the human intracellular protein termed CD2 binding protein 2 (CD2BP2), which binds to a site containing two tandem PPPGHR segments within the cytoplasmic region of CD2. Binding experiments and mutational analyses have demonstrated the critical importance of the GYF tripeptide in ligand binding. A GYF domain is also found in several other eukaryotic proteins of unknown function . It has been proposed that the GYF domain found in these proteins could also be involved in proline-rich sequence recognition .

Resolution of the structure of the CD2BP2 GYF domain by NMR spectroscopy revealed a compact domain with a β-β-α-β-β topology, where the single α-helix is tilted away from the twisted, anti-parallel β-sheet. The conserved residues of the GYF domain create a contiguous patch of predominantly hydrophobic nature which forms an integral part of the ligand-binding site . There is limited homology within the C-terminal 20-30 amino acids of various GYF domains, supporting the idea that this part of the domain is structurally but not functionally important .

This entry also matches Arabidopsis histone methyltransferases ATXR3/SDG2 and ATXR7/SDG25, which contain two partial GYF domains towards the N terminus . Histone methyltransferase ATXR7 is involved in regulation of flowering time . It is specifically required for the trimethylation of 'Lys-4' of histone H3 (H3K4me3) at the FLC locus, it prevents the trimethylation on 'Lys-27' (H3K27me3) at the same locus. ATXR3 is also required for H3K4 trimethylation and is crucial for both sporophyte and gametophyte development in plants .
S-locus-specific glycoprotein/EP1 (SLSG/EP1)
Type: Family

In Brassica species, S locus glycoproteins (SLGs) are involved in self-incompatibility, a mechanism that regulates the acceptance or rejection of pollen to prevent self-fertilization . SLGs accumulate in papillar cells of the stigma, at the site where inhibition of self-pollen tube development has been shown to occur .

This family also includes related proteins from Arabidopsis and epidermis-specific secreted glycoprotein EP1 from carrot, which has sequence homology to Brassica SLGs. EP1 is not involved in self-incompatibility, and its expression in seedlings rules out an specific role in pollination. Its role is not clear .
DNA topoisomerase I, N-terminal domain superfamily (DNA_topo_I_N_sf)
Type: Homologous_superfamily

Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB . They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases . The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases .

This superfamily represents the N-terminal domain of topoisomerase I from bacteria and virus .
Phosphoinositide 3-kinase, catalytic domain (PI3Kc)
Type: Domain

PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis .
SH3PXD2A, SH3 domain 3 (SH3PXD2A_SH3_3)
Type: Domain

This entry represents the third SH3 domain of SH3PXD2A.

Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells . It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion . Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
SH3PXD2A, SH3 domain 1 (SH3PXD2A_SH3_1)
Type: Domain

This entry represents the first SH3 domain of SH3PXD2A.

Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells . It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion . Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
Ada-like domain superfamily (Ada-like_dom_sf)
Type: Homologous_superfamily

The Escherichia coli Ada protein repairs O6-methylguanine residues and methyl phosphotriesters in DNA by direct transfer of the methyl group to a cysteine residue. This domain contains four conserved cysteines that form a zinc binding site . One of these cysteines is a methyl group acceptor. The methylated domain can then specifically bind to the ada box on a DNA duplex. The zinc binding site is located in the N-terminal region and consists of four β strands .

The methylation of the N-terminal site of Ada induces a structural change, which is independent of the transferred methyl group but enhances the promoter affinity of a remodeled surface region, trigger of the transcriptional enhancement of the ada regulon .

This superfamily represents the N-terminal domain of the Ada domain as well as the C-terminal domain of some ribosomal proteins (L17 from Actinobacteria and S1 from Candidatus Peregrinibacteria).
SH3PXD2A, SH3 domain 2 (SH3PXD2A_SH3_2)
Type: Domain

This entry represents the second SH3 domain of SH3PXD2A.

Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells . It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion . Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
SH3PXD2A, SH3 domain 4 (SH3PXD2A_SH3_4)
Type: Domain

This entry represents the fourth SH3 domain of SH3PXD2A.

Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells . It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion . Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
SH3PXD2A, SH3 domain 5 (SH3PXD2A_SH3_5)
Type: Domain

This entry represents the fifth SH3 domain of SH3PXD2A.

Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells . It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion . Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
SH3BP4, SH3 domain (SH3BP4_SH3)
Type: Domain

This entry represents the SH3 domain of SH3BP4 (SH3 domain-binding protein 4).

SH3BP4 binds to the inactive Rag GTPase complex through its Src homology 3 (SH3) domain and acts as a negative regulator of amino acid-Rag GTPase-mTORC1 signaling . It has been shown to act as an endocytic accessory protein that interacts with endocytic proteins including clathrin and dynamin, and regulates the internalization of the transferrin receptor (TfR) .
CRK, N-terminal SH3 domain (CRK_SH3_N)
Type: Domain

This entry represents the N-terminal SH3 domain found in the CRK family members .

CRK adaptor proteins consists of SH2 and SH3 domains, which bind tyrosine-phosphorylated peptides and proline-rich motifs, respectively. They function downstream of protein tyrosine kinases in many signaling pathways started by various extracellular signals, including growth and differentiation factors. Cellular CRK (c-CRK) contains a single SH2 domain, followed by N-terminal and C-terminal SH3 domains. It is involved in the regulation of many cellular processes including cell growth, motility, adhesion, and apoptosis. CRK has been implicated in the malignancy of various human cancers .

The N-terminal SH3 domain of CRK binds a number of target proteins including DOCK180, C3G, SOS, and cABL . The CRK family includes two alternatively spliced protein forms, CRKI and CRKII, that are expressed by the CRK gene, and the CRK-like (CRKL) protein, which is expressed by a distinct gene (CRKL). CrkI lacks the regulatory phosphorylation site and C-terminal SH3 domain present in CrkII and CrkL . The N-terminal SH3 domain of CRKII has been shown to bind the recognizes proline-rich motifs (PRMs) found in cABL kinase; this interaction is involved in the regulation of cell spreading, microbial pathogenesis, and cancer metastasis .
CRK, C-terminal SH3 domain (CRK_SH3_C)
Type: Domain

This entry represents the C-terminal SH3 domain found in the CRK family members .

CRK adaptor proteins consists of SH2 and SH3 domains, which bind tyrosine-phosphorylated peptides and proline-rich motifs, respectively. They function downstream of protein tyrosine kinases in many signaling pathways started by various extracellular signals, including growth and differentiation factors. Cellular CRK (c-CRK) contains a single SH2 domain, followed by N-terminal and C-terminal SH3 domains. It is involved in the regulation of many cellular processes including cell growth, motility, adhesion, and apoptosis. CRK has been implicated in the malignancy of various human cancers .

The C-terminal SH3 domain of CRK has not been shown to bind any target protein; it acts as a negative regulator of CRK function by stabilizing a structure that inhibits the access by target proteins to the N-terminal SH3 domain .
Bzz1, SH3 domain 1 (Bzz1_SH3_1)
Type: Domain

Bzz1 is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis . Together with other proteins, it induces membrane scission in yeasts .

Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This entry represents the first SH3 domain.
FCHSD, SH3 domain 1 (FCHSD_SH3_1)
Type: Domain

This entry represents the first SH3 domain found in the F-BAR and double SH3 domains proteins, including FCHSD1 and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains . FCHSD1 and FCHSD2 are expressed in cochlear sensory hair cells. FCHSD2 interacts with WASP and N-WASP, and stimulates F-actin assembly in vitro. FCHSD1 does not bind to WASP, but binds via its F-BAR domain to the SH3 domain of Sorting Nexin 9, a BAR protein that has been shown to promote WASP-Arp2/3-dependent F-actin polymerization . FCHSD2 has been implicated in receptor endocytosis and transport . The insect protein nervous wreck, which acts as a regulator of synaptic growth signaling , also contains this domain.
GmhA/DiaA (GmhA/DiaA)
Type: Family

Phosphoheptose isomerase (GmhA, LpcA) catalyzes the isomerization of sedoheptulose 7-phosphate into D-glycero-D-mannoheptose 7-phosphate. This is the first step of the biosynthesis of Gram-negative bacteria inner core lipopolysaccharide precursor, L-glycero-D-mannoheptose (Gmh) .

GmhA shows high similarity to Escherichia coli DnaA initiator-associating protein A (DiaA) , which is required for the timely initiation of chromosomal replication .
Eps8, SH3 domain (Eps8_SH3)
Type: Domain

This entry represents the SH3 domain found in Eps8 and Eps8-like proteins including Eps8-like 1-3. These proteins contain N-terminal phosphotyrosine-binding (PTB), central SH3, and C-terminal effector domains. The SH3 domains of Eps8 and similar proteins recognize peptides containing a PxxDY motif, instead of the classical PxxP motif .

Epidermal growth factor receptor kinase substrate 8 (EPS8) is a signalling adapter that possesses actin binding, bundling, and barbed-end capping activities . It forms a complex with Sos-1, Abi1 and the lipid kinase phosphoinositide 3-kinase (PI3-K) to regulate Rac activation that leads to actin cytoskeletal remodeling . It is critical for dendritic cell migration . It is involved in the initial growth of stereocilia in both inner hair cells and outer hair cells . It also regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF) . It has been linked to proliferation, metastasis and prognosis of many malignant tumours .
Peroxin 13 (Pex13)
Type: Family

Peroxin-13 (Pex13), located in the peroxisomal membrane, is a component of the peroxisomal translocation machinery with peroxin-14 and peroxin-17. Both termini of peroxin-13 are oriented to the cytosol. It is required for peroxisomal association of peroxin-14 . Both human and budding yeast Pex13 bind to the PTS1 signal recognition factor Pex5. However, they bind to Pex5 through different binding sites . In budding yeasts, Pex13 is also involved in the PTS2 signal recognition through its interaction with Pex7 .
AgaS, SIS domain (SIS_AgaS)
Type: Domain

AgaS contains a SIS (Sugar ISomerase) domain which is found in many phosphosugar isomerases and phosphosugar binding proteins. AgaS is a putative isomerase in Escherichia coli .
Rho GTPase-activating protein 9, SH3 domain (ARHGAP9_SH3)
Type: Domain

Rho GTPase-activating proteins (RhoGAPs or ARHGAPs) bind to Rho proteins and enhance the hydrolysis rates of bound GTP. ARHGAP9 functions as a GAP for Rac and Cdc42, but not for RhoA . It negatively regulates cell migration and adhesion . It also acts as a docking protein for the MAP kinases Erk2 and p38alpha, and may facilitate cross-talk between the Rho GTPase and MAPK pathways to control actin remodeling . It contains SH3, WW, Pleckstin homology (PH), and RhoGAP domains.
GlmS/AgaS, SIS domain 1 (GlmS/AgaS_SIS)
Type: Domain

AgaS is a putative isomerase in Escherichia coli . It is similar to glucosamine-6-phosphate synthases (GlmS), which catalyzes the first step in hexosamine metabolism. GlmS converts fructose 6-phosphate into glucosamine 6-phosphate using glutamine as nitrogen source .

GlmS contains a N-terminal glutaminase domain and two C-terminal SIS (Sugar ISomerase) domains. This domain is the first SIS domain found in GlmS and AgaS.
Putative ATP-dependent RNA helicase YLR419W-like, UBA domain (YLR419W-like_UBA)
Type: Domain

This entry represents the UBA domain found in some uncharacterised hypothetical proteins which show a high level of sequence similarity with Saccharomyces cerevisiae putative ATP-dependent RNA helicase YLR419W . All family members contain a ubiquitin-associated (UBA) domain, RWD domain, DEAD-box (DEXDc), helicase superfamily C-terminal domain (HELICc), Helicase associated domain (HA2), and a C-terminal oligonucleotide/oligosaccharide-binding (OB)-fold.
SH3D21, SH3 domain (SH3D21_SH3)
Type: Domain

This entry represents the N-terminal SH3 domain of the uncharacterised protein SH3 domain-containing protein 21, and similar uncharacterised proteins.
Amphiphysin I, SH3 domain (Amphiphysin_I_SH3)
Type: Domain

This entry represents the SH3 domain found in Amphiphysin I.

Amphiphysins function primarily in endocytosis and other membrane remodeling events . They exist in several isoforms and mammals possess two amphiphysin proteins from distinct genes. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin, and synaptojanin . They function in synaptic vesicle endocytosis. Human autoantibodies to amphiphysin I hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome .
Amphiphysin 2, SH3 domain (Amphiphysin-2_SH3)
Type: Domain

Amphiphysin 2, also known as Bin1, is localized in many different tissues and may function in intracellular vesicle trafficking . It plays a role in the organization and maintenance of the T-tubule network in skeletal muscle . Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy . Bin1 contains an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR) and a C-terminal SH3 domain.

The SH3 domain of Bin1 forms transient complexes with actin, myosin filaments, and CDK5, to facilitate sarcomere organization and myofibre maturation . It also binds dynamin and prevents its self-assembly .
RpiR-like, SIS domain (RpiR-like_SIS)
Type: Domain

RpiR contains a SIS (Sugar ISomerase) domain, which is found in many phosphosugar isomerases and phosphosugar binding proteins. In E. coli, RpiR negatively regulates the expression of rpiB gene. Both rpiB and rpiA are ribose phosphate isomerases that catalyze the reversible reactions of ribose 5-phosphate into ribulose 5-phosphate .

This domain is also found in other members of the RpiR family of transcriptional regulators, such as MurR and in uncharacterised proteins of the UPF0309 family.