SII-SWORD/CoKE huggingface dataset:
BCAR1, C-terminal (BCAR1_C)
Type: Domain

Breast cancer anti-estrogen resistance protein 1 (BCAR1, also known as p130Cas)
is a member of the Cas (Crk-associated substrate) family of adaptor proteins, which function as key signalling nodes with important regulatory roles in normal and pathological cells . BCAR1 plays a central coordinating role for tyrosine kinase-based signalling through focal adhesion kinase (FAK) . It is readily phosphorylated by FAK and Src . Overexpression of BCAR1 confers anti-estrogen resistance on breast cancer cells . It regulates the tumour suppressor function of TGF-beta during breast cancer progression through regulation of Smad2/3 activity .

This entry represents the FAT-like C-terminal domain of BCAR1, which binds to the C-terminal domain of NSPs (novel SH2-containing proteins) to form multidomain signaling modules that mediate cell migration and invasion.
rRNA (guanine-N(2)-)-methyltransferase RsmC/RlmG (RsmC/RlmG)
Type: Family

This family includes rRNA (guanine-N(2)-)-methyltransferases RsmC and RlmG whose structures are closely related and consist of two homologous domains; the N-terminal domain is involved in the recognition and binding of the substrate, and the C-terminal domain (CTD) mediates AdoMet-binding and the catalytic process . This entry also includes the uncharacterised proteins MJ0882 and YbxB, which are probable methyltransferases.

RlmG is a specific AdoMet-dependent methyltransferase responsible for N2-methylation of G1835 in 23S rRNA, while RsmC specifically methylates the guanine in position 1207 of 16S rRNA in the 30S particle.
MTMR4, FYVE domain (MTMR4_FYVE)
Type: Domain

Myotubularin-related protein 4 (MTMR4) is a member of the myotubularin (MTM) family. It is the only family member that possesses a FYVE domain (a zinc finger domain) at its C terminus . MTMR4 has dual-specificity phosphatase activity that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate . MTMR4 has a unique distribution to endosomes and has been shown to function in early and recycling endosomes ; through phosphatidylinositol 3-phosphate turnover in phagosome membranes regulates phagocytosis and phagosome maturation . MTMR4 attenuates TGF-beta signalling by dephosphorylating intracellular signalling mediator R-Smads . Similarly, it acts as a negative modulator for the homeostasis of bone morphogenetic proteins (BMPs) signalling .

This entry represents the C-terminal FYVE domain of MTMR4.

The myotubularin family constitutes a large group of conserved proteins, with 14 members in humans consisting of myotubularin (MTM1) and 13 myotubularin-related proteins (MTMR1-MTMR13). Orthologues have been found throughout the eukaryotic kingdom, but not in bacteria. MTM1 dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) to phosphatidylinositol and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] to phosphatidylinositol 5-monophosphate (PI5P) [

,

, . The substrate phosphoinositides (PIs) are known to regulate traffic within the endosomal-lysosomal pathway . MTMR1, MTMR2, MTMR3, MTMR4, and MTMR6 have also been shown to utilise PI(3)P as a substrate, suggesting that this activity is intrinsic to all active family members. On the other hand, six of the MTM family members encode for catalytically inactive phosphatases. Inactive myotubularin phosphatases contain substitutions in the Cys and Arg residues of the Cys-X5-Arg motif. MTM pseudophosphatases have been found to interact with MTM catalytic phosphatases . The myotubularin family includes several members mutated in neuromuscular diseases or associated with metabolic syndrome, obesity, and cancer .
Polycomb group RING finger protein 6, RAWUL (PCGF6_RAWUL)
Type: Domain

Polycomb group RING finger protein 6 (PCGF6 or MBLR) is a transcriptional repressor . It may activate KDM5D histone demethylase, which modulates the levels of histone H3K4Me3 . PCGF6 is a component of the Polycomb group (PcG) multiprotein PRC1-like complex , in which it regulates RNF2 ubiquitin ligase activity , and the E2F6.com-1 complex . PCGF6 contains a RING-type zinc finger.

This entry represents the RING finger- and WD40-associated ubiquitin-like (RAWUL) domain of PCGF6.
Glutathione-regulated potassium-efflux system ancillary protein KefG/KefF (KefG/KefF)
Type: Family

This family includes the glutathione-regulated potassium-efflux system ancillary proteins KefG and KefF which belong to the NAD(P)H dehydrogenase (quinone) family. The potassium efflux system (Kef) is used for many bacteria to protect themselves from the toxic effects of electrophilic compounds . This family also includes poorly characterised proteins, such as YrkL and YdeQ.
Glucose-1-phosphate cytidylyltransferase (G1P_cyt_trans)
Type: Family

Members of this family are the enzyme glucose-1-phosphate cytidylyltransferase, also called CDP-glucose pyrophosphorylase, the product of the rfbF gene. It is involved in the biosynthesis of the tyvelose, a 3,6-dideoxyhexose found in the O-antigen of the surface lipopolysaccharides .
Bridging integrator 3/RVS161-like (BIN3/RVS161-like)
Type: Family

This family includes a group of BAR-domain containing proteins, including BIN3 from human, its homologues RVS161 and hob3 from S. cerevisiae and S. pombe, respectively, and related proteins, which contain the N-BAR domain, related to the amphiphysin family of proteins . BIN3 is widely expressed in many tissues except in the brain. It plays roles in regulating filamentous actin localization and in cell division .

This entry also includes reduced viability upon starvation protein 167 (RVS167) from S. cerevisiae and its homologue in S. pombe, hob1 . RVS161/167 are components of a cytoskeletal structure that is required for the formation of endocytic vesicles at the plasma membrane level and form a complex that regulates actin, endocytosis, and viability following starvation or osmotic stress. Hob1 is structurally similar to RVS167, while hob3 is more similar to human BIN3 and RVS161, however, neither hob1 nor hob3 is required for endocytosis, . Hob1 is dispensable for endocytosis, actin organization, or osmotic sensitivity but it participates in DNA damage signalling as a part of stress response processes.
Bridging integrator 2, BAR domain (BAR_Bin2)
Type: Domain

Bridging integrator 2 (Bin2) is a BAR domain containing protein that is mainly expressed in hematopoietic cells . It is upregulated during granulocyte differentiation and is thought to function primarily in this lineage. It promotes cell motility and migration, probably via its interaction with the cell membrane and with podosome proteins that mediate interaction with the cytoskeleton. Bin2 modulates membrane curvature, mediates membrane tubulation and it plays a role in podosome formation. It was shown to inhibit phagocytosis .

The BAR domain of Bin2 is closely related to the BAR domains of amphiphysins, which function primarily in endocytosis and other membrane remodelling events. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. Unlike amphiphysins, Bin2 does not appear to contain a C-terminal SH3 domain. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), function in intracellular vesicle trafficking. Bin2 can form a stable complex with Bin1 in cells but cannot replace the function of Bin1, and thus, appears to harbour a nonredundant function .
Inositol 5-phosphatase (IP5)
Type: Family

This entry represents a family inositol 5-phosphatases and similar proteins predominantly found in eukaryotes including Synaptojanin-1 (SYNJ1), phosphatidylinositol 4,5-bisphosphate 5-phosphatase A (PI5PA) and inositol polyphosphate 5-phosphatase OCRL from humans. These enzymes act on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate . OCRL regulates traffic in the endosomal pathway by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with endosomes and is involved in primary cilia assembly . This protein is associated with the oculocerebrorenal syndrome of Lowe and Dent disease 2 .
Growth factor receptor-bound protein 7, RA domain (GRB7_RA)
Type: Domain

Grb7 (growth factor receptor bound protein 7) is an adapter protein mediating signal transduction from multiple cell surface receptors to diverse downstream pathways . It contains a Ras-associating (RA) domain, a pleckstrin-homology (PH) domain, a family-specific BPS (between PH and SH2) region and a C-terminal SH2 domain .

This entry represents the Ras-associating (RA) domain of Grb7.
Unconventional class IX myosin (Myo9)
Type: Family

Myosin IX (Myo9) is a processive single-headed motor, which might play a role in signalling. Class IX myosins contain a GTPase-activating protein (GAP) domain in their tail region, which allows them to negatively regulate small Rho GTPases . This entry includes unconventional myosin-IXb and unconventional myosin-IXa .

Myosin-IXb plays a role in the regulation of cell migration via its role as RHOA GTPase activator. This is regulated by its interaction with the SLIT2 receptor ROBO1; interaction with ROBO1 impairs interaction with RHOA and subsequent activation of RHOA GTPase activity, and thereby leads to increased levels of active, GTP-bound RHOA .

Myosin-IXa is highly expressed in the brain and binds the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) GluA2 subunit, and plays a key role in controlling the molecular structure and function of hippocampal synapses . Moreover, Myosin-IXa functions in epithelial cell morphology and differentiation such that its knockout mice develop hydrocephalus and kidney dysfunction . Myosin-IXa regulates collective epithelial cell migration by targeting RhoGAP activity to cell-cell junctions. Myosin-IXa negatively regulates Rho GTPase signalling, and functions as a regulator of kidney tubule function .
Unconventional myosin-IXb, RA domain (RA_Myosin-IXb)
Type: Domain

Myosin-IXb, also termed myosin-9b (Myo9b), is a motor protein with a Rho GTPase activating domain (RhoGAP); it is an actin-dependent motor protein of the unconventional myosin IX class [

. It is expressed abundantly in tissues of the immune system, like lymph nodes, thymus, and spleen and in several immune cells including dendritic cells, macrophages and CD4 . Myosin-IXb contains a Ras-associating (RA) domain, a motor domain, a protein kinase C conserved region 1 (C1), and a RhoGAP domain .

This entry represents the RA domain, which is located at its head domain and has the β-grasp ubiquitin-like fold with unknown function. Myosin-IXb acts as a motorized signalling molecule that links Rho signalling to the dynamic actin cytoskeleton. It regulates leukocyte migration by controlling RhoA signalling. Myosin-IXb is also involved in the development of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes . Moreover, Myosin-IXb is a ROBO-interacting protein that suppresses RhoA activity in lung cancer cells .
Unconventional myosin-IXa, Rho-GAP domain (RhoGAP_myosin_IX)
Type: Domain

Unconventional myosin-IXa (MYO9A) belongs to class IX myosin and contains a Ras-associating (RA) domain, a motor domain, a protein kinase C conserved region 1 (C1), and an extra Rho GTPase activating domain (RhoGAP) in the tail region . In mice, MYO9A homologue, Myr7 regulates Rho by stimulating its GTPase activity in neurons and has a role in the regulation of neuronal morphology and function . In humans, there are two proteins in class IX, MYO9A and MYO9B. Class IX myosins may carry its own Rho-GAP tail using its motor head domain to sites that require down-regulation of Rho-dependent signalling .

Myosin-IXa binds the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) GluA2 subunit, and plays a key role in controlling the molecular structure and function of hippocampal synapses [

. Moreover, Myosin-IXa functions in epithelial cell morphology and differentiation such that its knockout mice develop hydrocephalus and kidney dysfunction . Myosin-IXa regulates collective epithelial cell migration by targeting RhoGAP activity to cell-cell junctions. Myosin-IXa negatively regulates Rho GTPase signalling, and functions as a regulator of kidney tubule function .

This entry represents the RhoGAP domain of MYO9A.
Signal transducer and activator of transcription 4, coiled-coil domain (STAT4_CC)
Type: Domain

Signal transducer and activator of transcription 4 (STAT4) transduces interleukin-12, interleukin-23, and type I interferon cytokine signals in T cells and monocytes . It plays an important role in CD4+ Th1 lineage differentiation and IFN-gamma protein expression by CD4+ T cells . It is crucial for both innate and adaptive immune responses to viral infection . Variations of the STAT4 gene affect the susceptibility to autoimmune diseases , such as systemic lupus erythematosus 11 (SLEB11) and rheumatoid arthritis (RA) .

STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins . Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes . STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 .

This entry represents the coiled-coil (CCD or alpha) domain of STAT4.
Regulator of G-protein signaling 14, Ras-binding domain 1 (RBD1_RGS14)
Type: Domain

RGS14 is a regulator of G protein signaling (RGS) protein and contains an N-terminal RGS domain, two tandem Ras-binding domains (RBDs) and a G protein regulatory (GPR, also referred to as a GoLoco) motif. It regulates G protein nucleotide exchange and hydrolysis by acting as a GTPase-activating protein (GAP) through its RGS domain, and as a guanine nucleotide dissociation inhibitor (GDI) through its GoLoco motif . Both domains of RGS14 target members of the Gialpha subclass . It is a microtubule-associated protein that may modulate microtubule dynamics and spindle formation and play an essential role during mammalian cell division . RGS14 regulates the activation of alphaMbeta2 integrin during phagocytosis . It is a key regulator of signalling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory .

RGS14 binds activated H-Ras-GTP through its first RBD and interacts with Rap2-GTP and RAF kinases by the second tandem RBD. This entry represents the first RBD. RBD is structurally similar to the β-grasp fold of ubiquitin, a common structure involved in protein-protein interactions. RGS14 modulates neuronal physiology and all of its binding partners have roles in synaptic plasticity .
Regulator of G protein signaling 14, Ras-binding domain 2 (RBD2_RGS14)
Type: Domain

RGS14 is a regulator of G protein signaling (RGS) protein and contains an N-terminal RGS domain, two tandem Ras-binding domains (RBDs) and a G protein regulatory (GPR, also referred to as a GoLoco) motif. It regulates G protein nucleotide exchange and hydrolysis by acting as a GTPase-activating protein (GAP) through its RGS domain, and as a guanine nucleotide dissociation inhibitor (GDI) through its GoLoco motif . Both domains of RGS14 target members of the Gialpha subclass . It is a microtubule-associated protein that may modulate microtubule dynamics and spindle formation and play an essential role during mammalian cell division . RGS14 regulates the activation of alphaMbeta2 integrin during phagocytosis . It is a key regulator of signalling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory .

RGS14 binds activated H-Ras-GTP through its first RBD and interacts with Rap2-GTP and RAF kinases by the second tandem RBD. This entry represents the second RBD. RBD is structurally similar to the β-grasp fold of ubiquitin, a common structure involved in protein-protein interactions. RGS14 modulates neuronal physiology and all of its binding partners have roles in synaptic plasticity .
STAT5a/5b, coiled-coil domain (STAT5_CC)
Type: Domain

STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins . Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes . STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 .

STAT5 is a member of the STAT family of transcription factors. Two highly related proteins, STAT5a and STAT5b are encoded by separate genes, but are 90% identical at the amino acid level. Both STAT5a and STAT5b are ubiquitously expressed and functionally interchangeable. They regulate B and T cell development . These proteins are central signalling molecules in leukaemias driven by Abelson fusion tyrosine kinases, having a key role in resistance of leukaemic cells against treatment with tyrosine kinase inhibitors (TKI) . They differentially regulate cellular behaviour in human mammary carcinoma .

This entry represents the coiled--coil domain (CCD) of STAT5.
Regulator of G-protein signaling 10/12/14-like (RGS10/12/14-like)
Type: Family

RGS (Regulator of G protein Signalling) proteins are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways. Upon activation by GPCRs, heterotrimeric G proteins exchange GDP for GTP, are released from the receptor, and dissociate into free, active GTP-bound alpha subunit and beta-gamma dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the alpha subunit, which can then bind the beta-gamma dimer and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound alpha subunits by stabilising the G protein transition state . The human genome encode more than three dozen RGS domain-containing proteins with varied G-alpha substrate specificities, and are classified in eight different subfamilies: A or RZ; B or R4; C or R7; D or R12; E or RA; F or GEF; G or GRK (GPCR kinase) and H or SNX (sorting nexin) .

This entry represents the R12 RGS subfamily, which includes RGS10, RGS12 and RGS14 proteins, all of which are highly selective for G-alpha-i1 over G-alpha-q. This entry also includes regulator of G-protein signalling loco from Drosophila melanogaster, which is an RGS14 orthologue.
GGA3, VHS domain (VHS_GGA3)
Type: Domain

ADP-ribosylation factor-binding protein GGA3, also known as golgi-localised gamma ear-containing ARF-binding protein 3, plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. It is required for the lysosomal degradation of BACE (beta-site APP-cleaving enzyme), the protease that initiates the production of beta-amyloid, which causes Alzheimer's disease . It also plays a key role in GABA transmission, which is important in the regulation of anxiety-like behaviours . GGA3 mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules . GGA3 belong to the GGA family of proteins, which have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain.

This entry represents the VHS domain, which has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-terminal of these proteins. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the Trans-Golgi Network and the endosomal system .
Isocitrate dehydrogenase/Hypothetical protein TT1725, C-terminal domain superfamily (Isocitrate_DH_TT1725_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal domain of Isocitrate dehydrogenase [NADP] from Rickettsia typhi and similar bacterial proteins. It is also found in the hypothetical protein TT1725 from Thermus thermophilus HB8. The sequence is conserved in three predicted prokaryotic proteins with unknown functions, including Deinococcus radiodurans, Stigmatella aurantiaca, and Mycobacterium leprae. The presence of positively-charged residues in the α1 helix suggests this region binds to a protein with a negatively charged region or to nucleic acids .
KMT2D, PHD5 domain (KMT2D_PHD5)
Type: Domain

Histone-lysine N-methyltransferase 2D (KMT2D, also known as MLL2;

) is a catalytic component of the MLL2/3 complex (also named ASCOM complex) and methylates 'Lys-4' of histone H3 (H3K4me). H3K4me represents a specific tag for epigenetic transcriptional activation. KMT2D is recruited by ESR1 and acts as a coactivator of the oestrogen receptor alpha . It functions as a scaffold protein for association with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX, being responsible for maintaining the stability of UTX. KMT2D plays critical roles in regulating development, differentiation, metabolism, and tumour suppression . KMT2D contains the catalytic domain SET, five plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, a RING finger, an HMG (high-mobility group)-binding motif, and two FY-rich regions.

This entry represents the fifth PHD domain of KMT2D.
KMT2D, PHD3 domain (KMT2D_PHD3)
Type: Domain

Histone-lysine N-methyltransferase 2D (KMT2D, also known as MLL2;

) is a catalytic component of the MLL2/3 complex (also named ASCOM complex) and methylates 'Lys-4' of histone H3 (H3K4me). H3K4me represents a specific tag for epigenetic transcriptional activation. KMT2D is recruited by ESR1 and acts as a coactivator of the oestrogen receptor alpha . It functions as a scaffold protein for association with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX, being responsible for maintaining the stability of UTX. KMT2D plays critical roles in regulating development, differentiation, metabolism, and tumour suppression . KMT2D contains the catalytic domain SET, five plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, a RING finger, an HMG (high-mobility group)-binding motif, and two FY-rich regions.

This entry represents the third PHD domain of KMT2D.
tRNA uridine 5-carboxymethylaminomethyl modification enzyme, C-terminal subdomain (MnmG_C_subdom)
Type: Domain

This entry represents the C-terminal subdomain of MnmG (also known as GidA). It consists of the last highly conserved 3 helices of the C-terminal domain, which are rather short and form a small bundle . MnmG is a tRNA modification enzyme found in bacteria and mitochondria that forms a complex with MnmE which is involved in the formation of methyluridine derivatives at the wobble uridine base in some tRNAs . Based on mutational analysis the C-terminal domain has been suggested to be implicated in binding of the D-stem of tRNA and to be responsible for the interaction with protein MnmE .