SII-SWORD/CoKE huggingface dataset:
WWC, C2 domain (C2_WWC)
Type: Domain

The WWC (WW-and-C2-domain-containing protein) family negatively regulates cell proliferation and organ growth by suppressing the transcriptional activity of YAP, a major effector of the Hippo pathway. They activate large tumour suppressor 1 and 2 kinases (LATS1/2), which in turn phosphorylates the transcriptional co-activator YAP . Their two amino terminal WW domains mediate binding to target proteins, whereas the internal C2 domain is required for membrane association. WWC family members include WWC1 (also known as KIBRA), WWC2 and WWC3 .

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. Whereas the majority of known C2 domains have a role in Ca2+-dependent vesicle membrane association, these protein modules are also involved in Ca2+-insensitive membrane targeting as well as in intracellular protein-protein interactions. The C2 domain of KIBRA has been shown to have Ca2+-dependent-binding specificity for monophosphorylated phosphatidylinositols .
Freud, C2 domain (C2_Freud)
Type: Domain

The cc2d1a gene family consists of two homologues, CC2D1A (Freud-1) and CC2D1B (Freud-2). Freud-1 is a calcium-regulated repressor of serotonine receptor 5-HT1A and dopamine-D2 receptor expression . Mutations in cc2d1a has been linked to nonsyndromic mental retardation .

CC2D1A/freud-1 and CC2D1B/freud-2 share conserved domains, including several DM14 domains that are specific to this protein family, a C-terminal helix-loop-helix domain, and a C2 domain. The Freud-1 C2 domain is thought to be calcium insensitive and it lacks several acidic residues that mediate calcium binding of the PKC C2 domain. In addition, it contains a poly-basic insert that is not present in calcium-dependent C2 domains and may function as a nuclear localization signal . The Freud-1 C2 domain appears to be essential for its DNA binding and repressor function; it may mediate protein-protein interactions .
RASA2, PH domain (RASA2_PH)
Type: Domain

GAP1 (GTPase-activating protein 1) family members include RASA2 (GAP1m), RASAL (RASAL1), GAP1(IP4BP or RASA3), and CAPRI (RASA4). They all display Ras GAP activity. With the exception of RASA2, they all possess an arginine finger-dependent GAP activity on Rap1 . They contain N-terminal tandem C2 domain repeats, a centrally located Ras-GAP domain, and a PH (pleckstrin homology) domain containing a Btk motif .

This entry represents the PH domain of Ras GTPase-activating protein 2 (RASA2, also known as GAP1m). The tandem C2 domains of RASA2, like those of GAP1IP4BP, do not contain the conserved C2 motif that is known to be required for calcium-dependent phospholipid binding. RASA2 is regulated by the binding of its PH domains to phophoinositides, PIP3 (phosphatidylinositol 3,4,5-trisphosphate) . It suppresses RAS, enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, allowing control of cellular proliferation and differentiation . RASA2 also binds to inositol 1,3,4,5-tetrakisphosphate (IP4) .
RASA3, PH domain (RASA3_PH)
Type: Domain

GAP1 (GTPase-activating protein 1) family members include RASA2 (GAP1m), RASAL (RASAL1), GAP1(IP4BP or RASA3), and CAPRI (RASA4). They all display Ras GAP activity. With the exception of RASA2, they all possess an arginine finger-dependent GAP activity on Rap1 . They contain N-terminal tandem C2 domain repeats, a centrally located Ras-GAP domain, and a PH (pleckstrin homology) domain containing a Btk motif .

This entry represents the PH domain of Ras GTPase-activating protein 3 (RASA3, also known as GAP1 or IP4BP). The RASA3 PH domain binds to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and I(1,3,4,5)P4 . Its C2 domains, like those of RASA2 (GAP1M), do not contain the C2 motif that is known to be required for calcium-dependent phospholipid binding .
C2CD3, C2 domain (C2_C2CD3)
Type: Domain

C2cd3 is a novel C2 domain-containing protein specific to vertebrates. C2cd3 functions in regulator of cilia formation, Hedgehog signaling, and mouse embryonic development . Mutations in C2cd3 mice resulted in lethality in some cases and exencephaly, a twisted body axis, and pericardial edema in others . It is required for centriole elongation . Mutations in the human C2cd3 gene cause Orofaciodigital syndrome 14, which is characterised by malformations of the face, oral cavity, and digits . It plays an important part in centriolar distal appendage assembly and ciliary vesicle docking in mammals .

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. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions .
RASAL, RasGAP domain (RASAL_RasGAP)
Type: Domain

GAP1 (GTPase-activating protein 1) family members include RASA2 (GAP1m), RASAL (RASAL1), GAP1(IP4BP or RASA3), and CAPRI (RASA4). They all display Ras GAP activity. With the exception of RASA2, they all possess an arginine finger-dependent GAP activity on Rap1 . They contain N-terminal tandem C2 domain repeats, a centrally located Ras-GAP domain, and a PH (pleckstrin homology) domain containing a Btk motif .

This entry represents the RasGAP domain of RASAL. RASAL, like Ca2+ -promoted Ras inactivator (CAPRI, or RASA4), is a cytosolic protein that undergoes a rapid translocation to the plasma membrane in response to receptor-mediated elevation in the concentration of intracellular free Ca2+, a translocation that activates its ability to function as a RasGAP. Its tandem C2 domains bind phospholipids upon an elevation in the intracellular free Ca2+ concentration ([Ca2+]i). CAPRI and RASAL differ in that CAPRI is an amplitude sensor while RASAL senses calcium oscillations . This difference between them resides not in their C2 domains, but in their PH domains leading to speculation that this might reflect an association with either phosphoinositides and/or proteins .
RASA4, PH domain (RASA4_PH)
Type: Domain

GAP1 (GTPase-activating protein 1) family members include RASA2 (GAP1m), RASAL (RASAL1), GAP1(IP4BP or RASA3), and CAPRI (RASA4). They all display Ras GAP activity. With the exception of RASA2, they all possess an arginine finger-dependent GAP activity on Rap1 . They contain N-terminal tandem C2 domain repeats, a centrally located Ras-GAP domain, and a PH (pleckstrin homology) domain containing a Btk motif .

This entry represents the PH domain of Ras GTPase-activating protein 4 (RASA4, also known as CAPRI). Both CAPRI and RASAL are calcium-activated RasGAPs that inactivate Ras at the plasma membrane. Its tandem C2 domains bind phospholipids upon an elevation in the intracellular free Ca2+ concentration ([Ca2+]i). CAPRI and RASAL differ in that CAPRI is an amplitude sensor while RASAL senses calcium oscillations . This difference between them resides not in their C2 domains, but in their PH domains leading to speculation that this might reflect an association with either phosphoinositides and/or proteins .
Protein kinase C-like, C2 domain (C2_fungal_PKC)
Type: Domain

Protein kinase C (PKC) is a member of a family of Ser/Thr phosphotransferases that are involved in many cellular signaling pathways. Fungi have only one or two PKCs in contrast to mammals, which have at least 9 . Saccharomyces cerevisiae contains a single PKC isozyme, Pkc1p, which contains all of the regulatory motifs found in mammalian PKCs . In addition to its main function in maintaining cell integrity, fungi PKCs have been implicated in the regulation of diverse processes such as the organization of the actin cytoskeleton, autophagy and apoptosis, cell cycle control, cytokinesis and genetic stability . PKC has two antiparallel coiled-coiled regions (ACC finger domain) known as HR1 (PKC homology region 1/ Rho binding domain) upstream of the C2 domain and two C1 domains downstream.

The C2 domain was first identified in PKC. 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, like those of PKC, are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions .

This entry represents the C2 domain of fungal PKC-like proteins.
SynGAP, PH domain (SynGAP_PH)
Type: Domain

RasSynGAP family members include SynGAP, DOC-2/DAB2-interacting protein (DAB2IP) and neuronal growth-associated protein (nGAP/RASAL2). They contain the PH domain, C2 domain and the RasGAP domain.

SynGAP (also known as SYNGAP1) is a negative regulator of Ras and Rap GTPases . It is s primarily expressed in the excitatory neurons in the brain. It has several isoforms, SYNGAP A, B and C, differing in their N-termini. A and B isoforms contain unique peptide sequence and a complete PH domain, whereas isoform C is a shorter, truncated protein with no unique peptide sequence and no PH domain . Mutations in the SynGAP gene cause mental retardation, autosomal dominant 5 .

This entry represents the PH domain of SynGAP.
SKAP family (SKAP_fam)
Type: Family

This entry represents the SKAP (Src kinase-associated phosphoprotein) family, whose members include SKAP1 and SKAP2. They are adaptor proteins that have been implicated in cell adhesion through their association to integrins and cytoplasmic actin . They contain an N-terminal coiled-coil conformation, a central PH domain and a C-terminal SH3 domain .

SKAP1 (also known as SKAP55) is required for microcluster persistence and movement, junctional stabilization, and integrin-independent adhesion via the T cell receptor (TCR). It interacts with RAPL and RIAM via its N-termianl dimerization (DM) domain. The K152 and D120 within the PH domain of SKAP55 regulate plasma membrane targeting and TCR-mediated activation of LFA-1 (lymphocyte function-associated antigen 1) .

SKAP2 (also known as RA70) is required for beta2 integrin-mediated neutrophil recruitment and functions .
Transcriptional activator Spt7 (Spt7)
Type: Family

This entry includes transcriptional activator Spt7, which is a component of the transcription regulatory histone acetylation complexes SAGA, SLIK and SALSA .

The transcription regulatory histone acetylation complex Spt-Ada-Gcn5 acetyltransferase (SAGA) is involved in RNA polymerase II-dependent transcriptional regulation of approximately 10% of yeast genes. SAGA preferentially acetylates histones H3 and H2B and deubiquitinates histone H2B . SAGA is known as PCAF in vertebrates and PCAF acetylates nucleosomal histone H3 . The SAGA complex consists of at least TRA1, CHD1, SPT7, TAF5, ADA3, SGF73, SPT20/ADA5, SPT8, TAF12, TAF6, HFI1/ADA1, UBP8, GCN5, ADA2, SPT3, SGF29, TAF10, TAF9, SGF11 and SUS1, and some of these components are present as two copies. The complex is built up from distinct modules, each of which has a separate function and crosslinks with either other proteins or other modules in the complex .
Serine/threonine-protein kinase N, C2 domain (C2_PKN)
Type: Domain

PKN is a lipid-activated serine/threonine kinase. It is a member of the protein kinase C (PKC) superfamily, but lacks a C1 domain. There are at least 3 different isoforms of PKN (PRK1/PKNalpha/PAK1; PKNbeta, and PRK2/PAK2/PKNgamma). The C-terminal region contains the Ser/Thr type protein kinase domain, while the N-terminal region of PKN contains three antiparallel coiled-coil (ACC) finger domains which are relatively rich in charged residues and contain a leucine zipper-like sequence. These domains binds to the small GTPase RhoA. Following these domains is a C2-like domain. Its C-terminal part functions as an auto-inhibitory region. PKNs are not activated by classical PKC activators such as diacylglycerol, phorbol ester or Ca2+, but instead are activated by phospholipids and unsaturated fatty acids .

The C2 domain was first identified in PKC. 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. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions .
C2CD5, C2 domain (C2_C2CD5)
Type: Domain

C2CD5, also known as CDP138 or KIAA0528, is a C2 domain-containing phosphoprotein. It is a substrate for protein kinase Akt2, and it may be involved in the regulation of GLUT4 vesicle-plasma membrane fusion in response to insulin. The C2 domain of C2CD5 was shown to be capable of binding Ca(2+) and lipid membranes . Other studies indicate that C2CD5 is a CDK5- and FIBP-interacting protein, forming a complex with these proteins that is involved in cell proliferation and migration .

This entry represents the C2 domain of C2CD5.
Tandem C2 domains nuclear protein, C2A domain (C2A_Tac2-N)
Type: Domain

Tac2-N (tandem C2 protein in nucleus) contains two C2 domains and a short C terminus including a WHXL motif, which are key in stabilizing transport vesicles to the plasma membrane by binding to a plasma membrane. However, unlike the usual carboxyl-terminal-type (C-type) tandem C2 proteins, it lacks a transmembrane domain, a Slp-homology domain, and a Munc13-1-interacting domain. Homology search analysis indicate that no known protein motifs are located in its N terminus, making Tac2-N a novel class of Ca2+-independent, C-type tandem C2 proteins .

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. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. 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 domain of Tac2-N.
OCRL1, PH domain (OCRL1_PH)
Type: Domain

OCRL1 hydrolyzes phosphatidylinositol 4,5-bisphosphate (PtIns(4,5)P2) and the signaling molecule phosphatidylinositol 1,4,5-trisphosphate (PtIns(1,4,5)P3), and thereby modulates cellular signaling events . OCRL1 resides on vesicular structures throughout the endosomal system and the Golgi complex, and is also present at the plasma membrane in membrane ruffles and at late-stage endocytic clathrin-coated pits. It binds clathrin, clathrin adaptors, several GTPases, and the endocytic proteins APPL1 and Ses1/2 . Mutations in the OCRL1 gene cause Lowe Syndrome, leading to cataracts, mental retardation and renal failure . Mutations in OCRL can also give rise to a milder pathology, Dent disease 2, which is characterised by renal Fanconi syndrome in the absence of extrarenal pathologies .

OCRL1 shares ~45% sequence identity with INPP5B (not included in this entry) and has the same domain organization. However, a loop in the Rho GAP domain contains a second clathrin box which is absent in INPP5B. INPP5B shares most interacting partners with OCRL, except for clathrin and the endocytic clathrin adaptor AP-2 .

This entry represents the PH domain of OCRL1 . The PH domain connects to the 5-phosphatase domain, which has a Dnase I-like fold .
Tandem C2 domains nuclear protein, C2B domain (C2B_Tac2-N)
Type: Domain

Tac2-N (tandem C2 protein in nucleus) contains two C2 domains and a short C terminus including a WHXL motif, which are key in stabilizing transport vesicles to the plasma membrane by binding to a plasma membrane. However, unlike the usual carboxyl-terminal-type (C-type) tandem C2 proteins, it lacks a transmembrane domain, a Slp-homology domain, and a Munc13-1-interacting domain. Homology search analysis indicate that no known protein motifs are located in its N terminus, making Tac2-N a novel class of Ca2+-independent, C-type tandem C2 proteins .

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. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. 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 of Tac2-N.
Rab11-family interacting protein class I (FIP_classI)
Type: Family

Rab GTPases recruit various effector proteins to organelles and vesicles. Rab11-family interacting proteins (FIPs) are involved in mediating the role of Rab11. FIPs can be divided into three classes: class I FIPs (Rip11/Rab11-FIP5, RCP/RAB11FIP1, and FIP2) which contain a C2 domain after N terminus of the protein, class II FIPs (FIP3 and FIP4) which contain two EF-hands and a proline rich region, and class III FIPs (FIP1) which exhibits no homology to known protein domains. All FIP proteins contain a highly conserved, 20-amino acid motif at the C terminus of the protein, known as Rab11/25 binding domain (RBD). Class I FIPs are thought to bind to endocytic membranes via their C2 domain, which interacts directly with phospholipids. Class II FIPs do not have any membrane binding domains leaving much to speculate about the mechanism involving FIP3 and FIP4 interactions with endocytic membranes . Class I FIPs, but not the class II FIPs, also interact with Rab14 .

The exact function of the Rab11 and FIP interaction is unknown, but there is speculation that it involves the role of forming a targeting complex that recruits a group of proteins involved in membrane transport to organelles. Recent studies have identified several Rab11-FIP complex-binding proteins that regulate distinct membrane traffic pathways .

This family consist of class I FIPs.
Ingression protein 1, C2 domain (C2_fungal_Inn1)
Type: Domain

Saccharomyces cerevisiae Inn1 associates with the contractile actomyosin ring at the end of mitosis and is needed for cytokinesis . The C2 domain of Inn1, located at the N terminus, is required for ingression of the plasma membrane. The C terminus is relatively unstructured and contains eight PXXP motifs that are thought to mediate interaction of Inn1 with SH3 domains in the cytokinesis proteins Hof1 (an F-BAR protein) and Cyk3 (whose overexpression can restore primary septum formation in Inn1Delta cells) as well as recruiting Inn1 to the bud-neck by binding to Cyk3 .
OCRL1/INPP5B, INPP5c domain (OCRL1/INPP5B_INPP5c)
Type: Domain

OCRL1 hydrolyzes phosphatidylinositol 4,5-bisphosphate (PtIns(4,5)P2) and the signaling molecule phosphatidylinositol 1,4,5-trisphosphate (PtIns(1,4,5)P3), and thereby modulates cellular signaling events . OCRL1 resides on vesicular structures throughout the endosomal system and the Golgi complex, and is also present at the plasma membrane in membrane ruffles and at late-stage endocytic clathrin-coated pits. It binds clathrin, clathrin adaptors, several GTPases, and the endocytic proteins APPL1 and Ses1/2 . Mutations in the OCRL1 gene cause Lowe Syndrome, leading to cataracts, mental retardation and renal failure . Mutations in OCRL can also give rise to a milder pathology, Dent disease 2, which is characterised by renal Fanconi syndrome in the absence of extrarenal pathologies .

OCRL1 shares ~45% sequence identity with INPP5B and has the same domain organization. However, a loop in the Rho GAP domain contains a second clathrin box which is absent in INPP5B. INPP5B shares most interacting partners with OCRL, except for clathrin and the endocytic clathrin adaptor AP-2 .

This entry represents the inositol polyphosphate 5-phosphatase (INPP5c) domain of OCRL1/INPP5B.