SII-SWORD/CoKE huggingface dataset:
FGD6, N-terminal PH domain (FGD6_N_PH)
Type: Domain

FGD6 is a member of the FGD family. It has been found to coordinate cell polarity and endosomal membrane recycling in osteoclasts . This entry represent the N-terminal PH domain of FGD6.

FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain .

PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner . They share little sequence conservation, but all have a common fold, which is electrostatically polarised. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity . PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane . A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signalling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes .
ARHGEF18, PH domain (ARHGEF18_PH)
Type: Domain

ARHGEF18 is a guanine nucleotide exchange factor that activates RhoA, a small GTPase protein that is a key component of tight junctions and adherens junctions . It is crucial for maintenance of polarity in the vertebrate retinal epithelium, and consequently is essential for cellular differentiation, morphology and eventually organ function . ARHGEF18 contains Dbl-homology (DH) and pleckstrin-homology (PH) domains which bind and catalyze the exchange of GDP for GTP on RhoA. This entry represents the PH domain of ARHGEF18.

PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner . They share little sequence conservation, but all have a common fold, which is electrostatically polarised. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity . PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane . A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signalling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes .
Small G protein signalling modulator 1/2, PH domain (SGSM1/2)
Type: Domain

Small G-protein signalling modulator 1/2 (also known as RUTBC2/1) bind to Rab9A via their Pleckstrin homology (PH) domain . RUTBC1 stimulates GTP hydrolysis by Rab32 and Rab33B , while RUTBC2 appears to be a GAP for Rab36, Rab9A and associated proteins controling the recycling of mannose-6-phosphate receptors from late endosomes to the trans-Golgi .

This entry represents the PH domain of RUTBC1/2.
Protein Dok-7 (Dok-7)
Type: Family

Dok-7 is a cytoplasmic adaptor protein and a member of the Dok family. It is a substrate of MuSK (a receptor tyrosine kinase) and an activator of MuSK's kinase activity . Mutations of the Dok-7 gene cause Myasthenic syndrome, congenital, 10 (CMS10), a form of congenital myasthenic syndrome, a group of disorders characterised by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin .

The Dok family adapters are phosphorylated by different protein tyrosine kinases. Dok proteins are involved in processes such as modulation of cell differentiation and proliferation, as well as in control of the cell spreading and migration The Dok protein contains an N-terminal pleckstrin homology (PH) domain followed by a central phosphotyrosine binding (PTB) domain, which has a PH-like fold, and a proline- and tyrosine-rich C-terminal tail. The PH domain binds to acidic phospholids and localizes proteins to the plasma membrane, while the PTB domain mediates protein-protein interactions by binding to phosphotyrosine-containing motifs .
Dok-7, PH domain (Dok-7_PH)
Type: Domain

Dok-7 is a cytoplasmic adaptor protein and a member of the Dok family. It is a substrate of MuSK (a receptor tyrosine kinase) and an activator of MuSK's kinase activity . Mutations of the Dok-7 gene cause Myasthenic syndrome, congenital, 10 (CMS10), a form of congenital myasthenic syndrome, a group of disorders characterised by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin .

The Dok family adapters are phosphorylated by different protein tyrosine kinases. Dok proteins are involved in processes such as modulation of cell differentiation and proliferation, as well as in control of the cell spreading and migration The Dok protein contains an N-terminal pleckstrin homology (PH) domain followed by a central phosphotyrosine binding (PTB) domain, which has a PH-like fold, and a proline- and tyrosine-rich C-terminal tail. The PH domain binds to acidic phospholids and localizes proteins to the plasma membrane, while the PTB domain mediates protein-protein interactions by binding to phosphotyrosine-containing motifs .

This entry represents the PH domain of Dok-7.
Dok-7, PTB domain (Dok-7_PTB)
Type: Domain

Dok-7 is a cytoplasmic adaptor protein and a member of the Dok family. It is a substrate of MuSK (a receptor tyrosine kinase) and an activator of MuSK's kinase activity . Mutations of the Dok-7 gene cause Myasthenic syndrome, congenital, 10 (CMS10), a form of congenital myasthenic syndrome, a group of disorders characterised by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin .

The Dok family adapters are phosphorylated by different protein tyrosine kinases. Dok proteins are involved in processes such as modulation of cell differentiation and proliferation, as well as in control of the cell spreading and migration The Dok protein contains an N-terminal pleckstrin homology (PH) domain followed by a central phosphotyrosine binding (PTB) domain, which has a PH-like fold, and a proline- and tyrosine-rich C-terminal tail. The PH domain binds to acidic phospholids and localizes proteins to the plasma membrane, while the PTB domain mediates protein-protein interactions by binding to phosphotyrosine-containing motifs .

This entry represents the PTB domain of Dok-7.
Extended synaptotagmin, C2B domain (Ext_Synaptotagmin_C2B)
Type: Domain

The extended-synaptotagmins derive their name from their partial domain structure similarity to the synaptotagmins, characterised by an N-terminal membrane anchor and cytosolically exposed C2 domains. Additionally they contain an SMP (synaptotagmin-like mitochondrial-lipid-binding protein) domain and multiple C2 domains (five in E-Syt1 and three in E-Syt2 and E-Syt3). However, the function of extended-synaptotagmins is different to that of synaptotagmins, which are involved in secretory vesicle tethering to the plasma membrane and exocytosis. The extended-synaptotagmins are located to the endoplasmic reticulum (ER), and tether this organelle to the plasma membrane via their C2 domains. They transport glycerolipids between the two bilayers via their lipid-harboring SMP domains. Ca2+ regulates their membrane tethering and lipid transport function .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This entry represents the second C2 domain in extendend synaptotagmins (and the second and fourth domains in extended E-Syt1), which have a type-I topology .
Dok1/2/3, PTB domain (Dok1/2/3_PTB)
Type: Domain

The Dok family adapters are phosphorylated by different protein tyrosine kinases. Dok proteins are involved in processes such as modulation of cell differentiation and proliferation, as well as in control of the cell spreading and migration The Dok protein contains an N-terminal pleckstrin homology (PH) domain followed by a central phosphotyrosine binding (PTB) domain, which has a PH-like fold, and a proline- and tyrosine-rich C-terminal tail. The PH domain binds to acidic phospholids and localizes proteins to the plasma membrane, while the PTB domain mediates protein-protein interactions by binding to phosphotyrosine-containing motifs .

There are 7 mammalian Dok member (Dok-1 to 7). Dok-1 and Dok-2 act as negative regulators of the Ras-Erk pathway downstream of many immunoreceptor-mediated signaling systems, and it is believed that recruitment of p120 rasGAP by Dok-1 and Dok-2 is critical to their negative regulation . Dok-3 is a negative regulator of the activation of JNK and mobilization of Ca2+ in B-cell receptor-mediated signaling, interacting with SHIP-1 and Grb2 .

This entry represents the PTB domain of Dok1/2/3.
Extended synaptotagmin, C-terminal C2 domain (C2C_KIAA1228)
Type: Domain

The extended-synaptotagmins derive their name from their partial domain structure similarity to the synaptotagmins, characterised by an N-terminal membrane anchor and cytosolically exposed C2 domains. Additionally they contain an SMP (synaptotagmin-like mitochondrial-lipid-binding protein) domain and multiple C2 domains (five in E-Syt1 and three in E-Syt2 and E-Syt3). However, the function of extended-synaptotagmins is different to that of synaptotagmins, which are involved in secretory vesicle tethering to the plasma membrane and exocytosis. The extended-synaptotagmins are located to the endoplasmic reticulum (ER), and tether this organelle to the plasma membrane via their C2 domains. They transport glycerolipids between the two bilayers via their lipid-harboring SMP domains. Ca2+ regulates their membrane tethering and lipid transport function .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This entry represents the C-terminal C2 domain in extendend synaptotagmins, which have a type-I topology .
Plc1, PH domain (Plc1_PH)
Type: Domain

Saccharomyces cerevisiae Plc1 is a homologue of the delta isoform of mammalian phosphoinositide-specific phospholipase C (PI-PLC) . It is required for the initial step of inositol polyphosphate (InsP) synthesis. It hydrolyzes phosphatidylinositol 4,5-biphosphate (PIP2) to generate the signaling molecules inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG) .
Tricalbin, C2D domain (C2D_Tricalbin)
Type: Domain

Tricalbins (Tcb1/2/3) are yeast orthologues of the extended synaptotagmins. Tricalbins contain a transmembrane domain in their N-termini and lipid-binding C2 domains in their long cytoplasmic carboxyl-termini. As extended synaptotagmins, tricalbins also possess a synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain that is found in proteins localized to ER-organelle contact sites . The ER-plasma membrane tethering function of tricalbins mediates the formation of ER-PM contacts sites which are thought to mediate transport glycerolipids between the two bilayers .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This entry contains the fourth C2 repeat of tricalbins, C2D, and has a type-II topology . The C2 domains of tricalbins 1 and 3 are calcium-dependent lipid-binding units comparable to mammalian synaptotagmin C2 domains, while tricalbin 2 does not seem to bind lipids in response to calcium signaling .
Coiled-coil domain-containing protein 54 (CCDC54)
Type: Family

The function of coiled-coil domain-containing protein 54 is not clear.
Uncharacterized protein At4g29660-like (At4g29660-like)
Type: Family

This entry represents a group of plant proteins, including At4g29660. Their function is not known.
Small lysine-rich protein 1 (SMKR1)
Type: Family

This entry includes small lysine-rich protein 1 (SMKR1) and related proteins. Their function is not clear.
Tricalbin, C2A domain (C2A_Tricalbin)
Type: Domain

Tricalbins (Tcb1/2/3) are yeast orthologues of the extended synaptotagmins. Tricalbins contain a transmembrane domain in their N-termini and lipid-binding C2 domains in their long cytoplasmic carboxyl-termini. As extended synaptotagmins, tricalbins also possess a synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain that is found in proteins localized to ER-organelle contact sites . The ER-plasma membrane tethering function of tricalbins mediates the formation of ER-PM contacts sites which are thought to mediate transport glycerolipids between the two bilayers .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This entry contains the first C2 repeat of tricalbins, C2A, and has a type-II topology . The C2 domains of tricalbins 1 and 3 are calcium-dependent lipid-binding units comparable to mammalian synaptotagmin C2 domains, while tricalbin 2 does not seem to bind lipids in response to calcium signaling .
Tricalbin, C2C domain (C2C_Tricalbin)
Type: Domain

Tricalbins (Tcb1/2/3) are yeast orthologues of the extended synaptotagmins. Tricalbins contain a transmembrane domain in their N-termini and lipid-binding C2 domains in their long cytoplasmic carboxyl-termini. As extended synaptotagmins, tricalbins also possess a synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain that is found in proteins localized to ER-organelle contact sites . The ER-plasma membrane tethering function of tricalbins mediates the formation of ER-PM contacts sites which are thought to mediate transport glycerolipids between the two bilayers .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This entry contains the third C2 repeat of tricalbins, C2C, and has a type-II topology . The C2 domains of tricalbins 1 and 3 are calcium-dependent lipid-binding units comparable to mammalian synaptotagmin C2 domains, while tricalbin 2 does not seem to bind lipids in response to calcium signaling .
Transmembrane protein C1orf162 (C1orf162)
Type: Family

The function of C1orf162 is not clear.
Protein CEBPZOS (CEBPZOS)
Type: Family

The function of CEBPZOS (CEBPZ opposite strand) is not clear.
Tricalbin, C2B domain (C2B_Tricalbin)
Type: Domain

Tricalbins (Tcb1/2/3) are yeast orthologues of the extended synaptotagmins. Tricalbins contain a transmembrane domain in their N-termini and lipid-binding C2 domains in their long cytoplasmic carboxyl-termini. As extended synaptotagmins, tricalbins also possess a synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain that is found in proteins localized to ER-organelle contact sites . The ER-plasma membrane tethering function of tricalbins mediates the formation of ER-PM contacts sites which are thought to mediate transport glycerolipids between the two bilayers .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This entry contains the second C2 repeat of tricalbins, C2B, and has a type-II topology . The C2 domains of tricalbins 1 and 3 are calcium-dependent lipid-binding units comparable to mammalian synaptotagmin C2 domains, while tricalbin 2 does not seem to bind lipids in response to calcium signaling .
Protein FAR-RED ELONGATED HYPOCOTYL 1 (FHY1)
Type: Family

This entry represents a group of plant proteins, including FHY1 (At2g37678) from Arabidopsis. Phytochrome A (phyA) is the photoreceptor in Arabidopsis that mediates the far-red light high radiance response. AtFHY1 is a key regulator of far red/red (FR/R) spectrum-specific responses by regulating phyA shuttling from the cytoplasm to the nucleus and by directly regulating the expression of some target genes. AtFHY1 phosphorylation is induced by the R signal, is part of the FR/R spectrum sensing mechanism that ensures its optimal response to specific light quality . AtFHY1 also has an independent role in gene modulation and plant development under far-red light .

This entry also includes FHL (FHY1 Like). FHL is essential for light-regulated PHYA nuclear accumulation and subsequent PHYA phototropic signaling processes . The transcription of FHY1 and FHL are controlled by FHY3 (Far-red elongated HYpocotyl 3) and FAR1 (FAr-red impaired Response 1), a related pair of transcription factors .
Mug190-like, C2A domain (C2A_Mug190-like)
Type: Domain

Meiotically up-regulated gene 190 protein (Mug190) from Schizosaccharomyces pombe derives its name from a study to identify genes essential for meiosis . It is thought to correspond to tricalbin 2 in Saccharomyces cerevisiae. Tricalbins are C2 domain proteins involved in ER-plasma membrane tethering .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This entry represents the first C2 repeat of Mug190, C2A, and has a type-II topology .
Copine, C2B domain (C2B_Copine)
Type: Domain

Copines are a widely distributed class of Ca2+-dependent lipid-binding proteins. Most have a characteristic domain structure: two C2 domains in the N-terminal region and a von Willebrand A (VWA) domain in the C-terminal region. They are potentially involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth . In plants, they are known as BONZAI proteins . The copine family in plants may have effects in promoting growth and development in addition to repressing cell death . Caenorhabditis elegans copine, also known as Nra1, is Involved in nicotinic acetylcholine receptor (nAChR)-mediated sensitivity to nicotine and levamisole .

C2 domains fold into an 8-standed β-sandwich that can adopt 2 structural arrangements: type I and type II, distinguished by a circular permutation involving their N- and C-terminal β strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This entry represents the second C2 repeat of copines, C2B, and has a type-I topology. The C2B domains of copine-2, copine-6 and copine-7 have been shown to be responsible for the protein calcium-dependent membrane association .
Abr/Bcr (Abr/Bcr)
Type: Family

Abr (active breakpoint cluster region-related protein) and Bcr (breakpoint cluster region protein) are homologous proteins containing a C-terminal domain with GTPase-activating protein (GAP) activity specific for Rac. They control multiple cellular functions of murine macrophages . They contain several domains, including tandem DH-PH, C2 and GAP domains. Bcr has an extra N-terminal oligomerization domain .
Cyclin-dependent kinase 7 (CDK7)
Type: Family

Cyclin-dependent kinase 7 (CDK7) is a serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription. It is activated by binding to a cyclin; binding to a different cyclin and phosphorylation of another kinase progresses the cell cycle. CDK7 binds cyclin-B and phosphorylates CDK1 during G2-M transition, and phosphorylates CDK2 and binds to cyclins during G1-S transition . CDK7 phosphorylates and activates p53 following DNA damage , but CDK7 is then inactivated by p53, which arrests the cell cycle, allowing the cell to recover or undergo apoptosis . CDK7 is also the catalytic subunit of the CDK-activating kinase (CAK) complex, which also contains cyclin-H (CCNH) and MAT1 . In turn, the CAK associates with the core-TFIIH to form the TFIIH basal transcription factor .

This entry includes CDK7 from animals, Kin28 from budding yeasts and Crk1 (also known as Mcs6) from fission yeasts. S. pombe possesses two CAKs, the nonessential Csk1 and the essential Mcs6 kinases, corresponding to the yeast Cak1 and the metazoan CDK7, respectively. Mcs6 modulates gene expression through both its CAK and CTD kinase activities . Kin28 is the closest homologue of CDK7 from budding yeasts. It forms a complex with Ccl1 and Tfb3. This complex associate with TFIIH for transcription regulating activity, but does not display CAK activity . Instead, Cak1, a single-subunit kinase distantly related to Cdk, catalyzes Cdk activation at both transitions of the budding yeast cell cycle .