The C2 domain is a Ca2+-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C and the protein kinase catalytic domain []. Regions with significant homology []to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding []and in membrane targetting processes such as subcellular localisation. The 3D structure of the C2 domain of synaptotagmin has been reported[], the domain forms an eight-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key []. Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca2+-binding loops are located at the end of an 8 stranded antiparallel β-sandwich.
This entry represents complement component C2, a component of the classical and lectin activation pathway of complement. C2 is cleaved by C1s (classical) or mannan-binding lectin-associated serine peptidases (lectin) into C2a and C2b []. C2a is a serine endopeptidase from family S1 (chymotrypsin family; MEROPS identifier S01.194) which complexes with C4b to form the C3/C5 convertase []. The complex is stabilized by Mg2+[, ]. The C3/C5 convertase has trypsin-like specificity []. C2 deficiency is the commonest human complement deficiency, which can result in systemic lupus erythematosus-like immune complex diseases []. The C2 gene is part of the major histocompatabaility complex [].
A C2 domain is usually involved in targeting proteins to cell membranes. This entry represents a C2 domain found in the CEP76 proteins []. CEP76 is a centrosomal protein involved in regulation of centriole duplication [].
Tac2-N (tandem C2 domains nuclear protein) represents a novel class of C-type tandem C2 proteins. Tac2-N proteins are almost exclusively localised in the nucleus [].
A C2 domain is usually involved in targeting proteins to cell membranes. Ciliary CC2D2A protein has two C2 domains and an inactive transglutaminase-like peptidase domain (CC2D2A-TGL) []. This entry represents the first C2 domain. CC2D2A (coiled-coil and C2 domain-containing protein 2A) is a component of the tectonic-like complex, a complex localised at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes []. It is required for ciliogenesis and sonic hedgehog/SHH signalling [].
Perforin-1 contains a single copy of a C2 domain in its C terminus and plays a role in lymphocyte-mediated cytotoxicity []. Mutations in perforin-1 lead to familial hemophagocytic lymphohistiocytosis type 2, a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines []. The function of perforin-1 is calcium dependent and the C2 domain is thought to confer this binding to target cell membranes []. 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 beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including 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 [, , , , , , , ].
A single C2 domain is found in calpains (EC 3.4.22.52, EC 3.4.22.53), calcium-dependent, non-lysosomal cysteine proteases.The C2 domain is a Ca2+-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C and the protein kinase catalytic domain []. Regions with significant homology []to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding []and in membrane targetting processes such as subcellular localisation. The 3D structure of the C2 domain of synaptotagmin has been reported[], the domain forms an eight-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key []. Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca2+-binding loops are located at the end of an 8 stranded antiparallel β-sandwich.
Tollip is a part of the Interleukin-1 receptor (IL-1R) signaling pathway. Tollip is proposed to link serine/threonine kinase IRAK to IL-1Rs as well as inhibiting phosphorylation of IRAK []. The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates []. There is a single C2 domain present in Tollip. 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 beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide varietyof substances including 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 [, , , , , , , ].
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 beta 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 [, , , ].
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 [].
The C2 domain is one of the most prevalent eukaryotic lipid-binding domains deployed in diverse functional contexts. Distinct versions of the C2 domain have been recognized, the classical C2, the PI3K-type, the tensin-type, the B9-type, the DOCK-type, the NT-type and the Aida-type. Despite their limited sequence similarity, all C2 domains contain at their core a compact β-sandwich composed of two four-stranded β-sheets with highly variable inter-strand regions that might contain one or more α-helices. One feature that is highly conserved in the C2 domains is the pair of hydrophobic residues on the upper part of the β-sheet, which are involved in imparting a curvature of the sheet that allows formation of a concave ligand-binding area [].This entry represents a family of B9-type C2 domain containing proteins, found in ciliary basal body associated proteins. Although its specific function is unknown, a cilia-specific role has been suggested for the poorly characterised B9-type C2 domain [, , ].Some proteins known to contain a B9-type C2 domain are listed below:Mammalian Tectonic-like complex member MKS1 (also known as Meckel syndrome 1 , MKS1). The tectonic-like complex is localised at the transition zone of primary cilia and acts as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. It is involved in centrosome migration to the apical cell surface during early ciliogenesis [, , ]. The homologue in Drosophila melanogaster is required for ciliary structure and function [, ]. Mammalian proteins B9D1 and B9D2. B9D1 is required for ciliogenesis and sonic hedgehog/SHH signaling [, ].
The C2 domain is one of the most prevalent eukaryotic lipid-binding domainsdeployed in diverse functional contexts. Many C2 domainsbind directly to membrane lipids and display a wide range of lipidselectivity, with preference for anionic phosphatidylserine (PS) andphosphatidylinositol-phosphates (PIPs).Despite their limited sequence similarity, all C2 domains contain at theircore a compact β-sandwich composed of two four-stranded beta sheets withhighly variable inter-strand regions that might contain one or more alpha-helices.The NT-type C2 domain shows a diverse range of domain architectures but it isnearly always found at the N-termini of proteins that contain it. Hence, ithas been named the N-terminal C2 (NT-C2) family. It is typically coupled witha coiled-coil domain, that could mediate di/oligo-merization and the DIL(Dilute) domain. It is also coupled with the Calponinhomology (CH) domain in EHBP1 proteins, Filamin/ABP280repeats and Mg2+ transporter MgtE N-terminal domain inproteins from chlorophyte algae such as Micromonas and Ostreococcus tauri.Thus, a common theme across the NT-type C2 domain proteins is the combinationto several different domains with microfilament-binding or actin-related roles(i.e. such as CH, DIL, and Filamin). Other conserved groups of the NT-type C2proteins prototyped by EEIG1, PMI1, and SYNC1 have their own distinct C-terminal conserved extensions that are restricted to these groups and mightmediate specific interactions. The primary function of the NT-type C2 domainappears to be the linking of actin/microfilament-binding adaptors to themembrane and to act as a link that tethers endosomal vesicles to thecytoskeleton in course of their intracellular trafficking [, ].
The C2 domain is a Ca2+-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C and the protein kinase catalytic domain []. Regions with significant homology []to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding []and in membrane targetting processes such as subcellular localisation. The 3D structure of the C2 domain of synaptotagmin has been reported[], the domain forms an eight-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key []. Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca2+-binding loops are located at the end of an 8 stranded antiparallel β-sandwich.
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.
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 [].
The function of C2 calcium-dependent domain-containing protein 4C/4D is not known. The C2 domain is a Ca2 -dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking.
The function of C2 calcium-dependent domain-containing protein 4C is not known. The C2 domain is a Ca2+-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking.
Ferlins are involved in vesicle fusion events []. Ferlins and other proteins, such as synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1).Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF [].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 beta 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 [, , ].This entry represents the second C2 repeat of ferlins, C2B, which has a type-II topology.
Ferlins are involved in vesicle fusion events []. Ferlins and other proteins, such as synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1).Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF [].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 beta 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 [, , ].This entry represents the third C2 repeat of ferlins, C2C, and has a type-II topology.
Ferlins are involved in vesicle fusion events []. Ferlins and other proteins, such as synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1).Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF [].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 beta 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 [, , ].This entry represents the fourth C2 repeat of ferlins, C2D, which has a type-II topology.
Ferlins are involved in vesicle fusion events []. Ferlins and other proteins, such as synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1).Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF [].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 beta 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 [, , ].This entry represents the fifth C2 repeat of ferlins, C2E, which has a type-II topology.
Ferlins are involved in vesicle fusion events []. Ferlins and other proteins, such as synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1).Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF [].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 beta 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 [, , ].This entry represents the sixth C2 repeat of ferlins, C2E, which has a type-II topology.
Ferlins are involved in vesicle fusion events []. Ferlins and other proteins, such as synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1).Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF [].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 beta 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 [, , ].This entry represents the first C2 repeat of ferlins, C2A, which has a type-II topology.
Neurotransmitter release from nerve termini in the brain is regulated by several families of Ca2+-binding proteins with tandem C2 domains () []. The C2 domain confers the ability to binding phospholipids in a Ca2+-dependent fashion.Doc2 (double C2-like domain-containing protein) has one Munc13-interacting domain (Munc13 is a peripheral membrane protein in the plasma membrane of nerve termini). The interaction between Doc2 and Munc13-1 is thought to underlie the molecular mechanism of phorbol ester enhancement of neurotransmitter release [].Doc2 consists of three isoforms, Doc2alpha, beta and gamma. Doc2alpha is specifically expressed in neuronal cells and has been implicated in Ca2+-dependent neurotransmitter release, whereas Doc2beta is ubiquitously expressed [, ]. In contrast to the other Doc2 isoforms, the C2 domains of Doc2gamma lacks the Ca2+-dependent phospholipid binding activity. The highest expression of Doc2gamma mRNA is found in the heart, but occurs ubiquitously, the same as Doc2beta. Doc2gamma may also function as an effector for Munc13-1 and may be involved in the regulation of vesicular trafficking [].
Tensins constitute an eukaryotic family of lipid phosphatases that are defined by thepresence of two adjacent domains: a lipid phosphatase domain and a C2-like domain. The tensin-type C2 domain has a structure similar to the classical C2 domain (see ) that mediates the Ca2+-dependent membrane recruitment of several signalling proteins. However the tensin-type C2 domain lacks two of the three conserved loops that bind Ca2+, and in this respect it is similar to the C2 domains of PKC-type [, ]. The tensin-type C2 domain can bind phopholipid membranes in a Ca2+ independent manner []. In the tumour suppressor protein PTEN, the best characterised member of the family, the lipid phosphatase domain was shown to specifically dephosphorylate the D3 position of the inositol ring of the lipid second messenger, phosphatydilinositol-3-4-5-triphosphate (PIP3). The lipid phosphatase domain contains the signature motif HCXXGXXR present in the active sites of protein tyrosine phosphatases (PTPs) and dual specificity phosphatases (DSPs). Furthermore, two invariant lysines are found only in the tensin-type phosphatase motif (HCKXGKXR) and are suspected to interact with the phosphate group at position D1 and D5 of the inositol ring [, ]. The C2 domain is found at the C terminus of the tumour suppressor protein PTEN (phosphatidyl-inositol triphosphate phosphatase). This domain may include a CBR3 loop, indicating a central role in membrane binding. This domain associates across an extensive interface with the N-terminal phosphatase domain DSPc suggesting that the C2 domain productively positions the catalytic part of the protein on the membrane. The crystal structure of the PTEN tumour suppressor has been solved []. The lipid phosphatase domain has a structure similar to the dual specificity phosphatase (see ). However, PTEN has a larger active site pocket that could be important to accommodate PI(3,4,5)P3. Proteins known to contain a phosphatase and a C2 tensin-type domain are listed below: Tensin, a focal-adhesion molecule that binds to actin filaments. It may be involved in cell migration, cartilage development and in linking signal transduction pathways to the cytoskeleton.Phosphatase and tensin homologue deleted on chromosome 10 protein (PTEN). It antagonizes PI 3-kinase signalling by dephosphorylating the 3-position of the inositol ring of PI(3,4,5)P3 and thus inactivates downstream signalling. It plays major roles both during development and in the adult to control cell size, growth, and survival.Auxilin. It binds clathrin heavy chain and promotes its assembly into regular cages.Cyclin G-associated kinase or auxilin-2. It is a potential regulator of clathrin-mediated membrane trafficking.
This is the C2 domain found in plant proteins, including SRC2 (Soybean genes Regulated by Cold 2) and BAP1/2 (BON1-associated protein 1/2), which are involved in defence responses [, ]. SRC2 is induced after pathogen infiltration and in cold conditions. Arabidopsis SRC2 homologue functions as a calcium-dependent activator of the NADPH oxidase AtRbohF, that mediates reactive oxygen species (ROS) production after cold induction. SRC2 contains a single C2 domain which localizes to the plasma membrane and is involved in Ca2+ dependent protein binding []. BAP1/2 are negative regulators of cell death and defense responses, as they repress the activity of disease resistance (R) genes [].
This entry includes C2 domain-containing protein 2 (C2CD2) and C2CD2-like (C2CD2L) proteins. C2CD2L, also known as TMEM24, is an endoplasmic reticulum (ER)-anchored membrane protein that binds lipids and transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]precursor phosphatidylinositol between bilayers, allowing replenishment of PI(4,5)P2 hydrolyzed during signaling []. The function of C2CD2 is not known.
The WWC (WW-and-C2-domain-containing protein) family negatively regulates cell proliferation and organ growth by suppressing the transcriptional activityof 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 beta 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 [].
This entry represents the C2 domain found in cytosolic phospholipase A2 (cPLA2), which hydrolyzes arachidonyl phospholipids in the sn-2 position releasing arachidonic acid. The cooperative binding of two Ca(2+) ions to the C2 domain of cPLA2-alpha induces docking to phosphatidylcholine (PC) membranes []. This domain have a type-II C2 domain topology. 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 beta 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 [, ].
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 beta 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.
Rho guanosine triphosphatases (GTPases) are critical regulators of cell motility, polarity, adhesion, cytoskeletal organisation, proliferation, geneexpression, and apoptosis. Conversion of these biomolecular switches to the activated GTP-bound state is controlled by two families of guanine nucleotide exchanges factors (GEFs). DH-PH proteins are a large group of Rho GEFs comprising a catalytic Dbl homology (DH) domain with an adjacent pleckstrin homology (PH) domain within the context of functionally diverse signalling modules. The evolutionarily distinct andsmaller family of DOCK (dedicator of cytokinesis) or CDM (CED-5, DOCK1180, Myoblast city) proteins activate either Rac or Cdc42 to control cell migration, morphogenesis, and phagocytosis. DOCK proteins share the DOCK-type C2 domain (also termed the DOCK-homology region (DHR)-1 or CDM-zizimin homology 1 (CZH1) domain and the DHR-2 domain (also termed the CZH2 or DOCKER domain), [, , , , , ].The ~200 residue DOCK-type C2 domain is located toward the N terminus. It adopts a C2-like architecture and interacts with phosphatidylinositol3,4,5-trisphosphate []to mediate signalling and membrane localization. The central core of the DOCK-type C2 domain domain adopts an antiparallel β-sandwich with the "type II"C2 domain fold (a circular permutation of the more common "type I"topology), in which two 4-stranded sheets with strand order 6-5-2-3 and 7-8-1-4 create convex- and concave-exposed faces, respectively [].Some DOCK proteins are listed below:Mammalian Mammalian dedicator of cytokinesis 180 (DOCK180 or DOCK1),important for cell migration.Mammalian DOCK2, important for lymphocyte development, homong, activation,adhesion, polarization and migration processes.Mammalian DOCK3 (also known as MOCA), is expressed predominantly in neuronsand resides in growth cones and membrane ruffles.Mammalian DOCK4, possesses tumor suppressor properties.Mammalian DOCK9 (zizimin1), plays an important role in dendrite growth inhippocampal neurons through activation of Cdc42.Drosophila melanogaster Myoblast city.Caenorhabditis elegans CED-5.
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that phosphorylate 4,5-bisphonate (PI(4,5) P2 or PIP2) at the 3-position of the inositol ring, and thus generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which, in turns, initiates a vast array of signaling events. PI3Ks can be grouped intothree classes based on their domain organisation. Class I PI3Ks are heterodimers consisting of a p110 catalytic subunit and a regulatory subunit of either the p85 type (associated with the class IA p110 isoforms p110alpha, p110beta or p110delta) or the p101 type (associated with the class IB p110isoform p110gamma). Common to all catalytic subunits are an N-terminal adaptor-binding domain (ABD) that binds to p85/p101, a Ras- binding domain (RBD), a putative membrane-binding domain (C2), a helical domain of unknown function, and a kinase catalytic domain. Class II PI3Ks lack the ABD domain and are distinguished by a carboxy terminal C2 domain. Class III enzymes lack the ABD and RBD domains [, , , ].The PI3K-type C2 domain is an eight-stranded antiparallel β-sandwich consisting of two four-stranded β-sheets [, , , ].
C2 calcium-dependent domain-containing protein 4A (NLF1) and 4B (NLF2) are nuclear factors highly expressed in endothelial cells and induced by acute inflammation. They may have a role in regulating genes that control cellular architecture and adhesion [].
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 beta 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 [, , ,].
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 beta 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 [].
This domain is the first, more N-terminal, C2 domain on X-linked retinitis pigmentosa GTPase regulator-interacting proteins, or RPGR-interacting proteins [].
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 beta 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.
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 beta 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.
Domain C2 of tRNA-guanine transglycosylase is formed by a four-stranded anti-parallel β-sheet lined with two alpha helices. It has conserved basic residues on the surface of the β-sheets as does the C-terminal domain PUA (). The catalytic domain of TGT has conserved basic residues on the outer surface of the N-terminal three-stranded beta sheet, which closes the barrel. It is postulated that these basic residues from the three domains form a continuous, positively charged patch to which the tRNA binds [].
Archaeosine tRNA-guanine transglycosylase (ArcTGT) is made of an N-terminal catalytic domain and a C-terminal region with unidentified functions. The C-terminal region is divided into three domains, C1, C2, and C3. The catalytic domain of TGT has conserved basic residues on the outer surface of the N-terminal three-stranded beta sheet, which closes the barrel. It is postulated that these basic residues from the three domains form a continuous, positively charged patch to which the tRNA binds [].This superfamily represents domain C2 of ArcTGT, formed by a four-stranded anti-parallel β-sheet lined with two alpha helices. It has conserved basic residues on the surface of the β-sheets as does the C-terminal domain PUA () [].
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 [, ]. Inn1 and Cyk3 appear to cooperate in activating chitin synthase Chs2 for primary septum formation, which allows coordination of actomyosin ring contraction with ingression of the cleavage furrow []. It is thought that the C2 domain of Inn1 helps to preserve the link between the actomyosin ring and the plasma membrane, contributing both to membrane ingression, as well as to stability of the contracting ring. Additionally, Inn1 might induce curvature of the plasma membrane adjacent to the contracting ring, thereby promoting ingression of the membrane []. S. pombe Inn1 is also involved in the ingression of the plasma membrane during cytokinesis. However, it does not play an essential role, probably because the actinomyosin ring is connected to the cell cortex by many more proteins [].
This entry includes coiled-coil and C2 domain-containing protein 1A/B (CC2D1A/B, also known as Freud-1/2). CC2D1A is involved in many pathways, including nuclear factor kappaB, PDK1/Akt, cAMP/PKA, Notch and bone morphogenetic protein []. It is a calcium-regulated repressor of serotonine receptor 5-HT1A and dopamine-D2 receptor expression [, ]. CC2D1B binds to the 5-HT1A DRE and represses the human 5-HT1A receptor gene to regulate its expression in non-serotonergic cells and neurons [].CC2D1A and CC2D1B have also been shown to interact with the CHMP4 family of proteins, the major subunit of the ESCRT-III complex. They may regulate degradation and signaling of EGFR and TLR4 [].CC2D1A and CC2D1B 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 CC2D1A 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 CC2D1B C2 domain appears to be essential for its DNA binding and repressor function; it may mediate protein-protein interactions []. Mutations in the CC2D1A gene has been linked to nonsyndromic mental retardation [, ].
HECW1 (HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1), also known as NEDL1, is an HECT-type E3 ubiquitin protein ligase highly expressed in favorable neuroblastomas []. NEDL1 is thought to normally function in the quality control of cellular proteins by eliminating misfolded proteins. This is thought to be accomplished via a mechanism analogous to that of ER-associated degradation by forming tight complexes and aggregating misfolded proteins that have escaped ubiquitin-mediated degradation []. NEDL1 is thought to stimulate p53-mediated apoptosis [].NEDL1 shares large homology and structure with NEDL2, including a C2 domain at the N terminus, two WW domains in the middle of the protein, and a HECT domain at the C terminus []. NEDL2 regulates the stability of p73 []and functions as a regulator of the metaphase to anaphase transition [].This entry represents the C2 domain of NEDL1 and NEDL2.
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents the C2 domain found in the Dock-C members. In addition to the C2 domain (also known as DHR-1 domain) and the DHR-2 domain, Dock-C members contain a functionally uncharacterised domain upstream of the C2 domain. DHR-2 has the catalytic activity for Rac and/or Cdc42, but is structurally unrelated to the DH domain. The C2/DHR-1 domains of Dock1 (also known as Dock180) and Dock4 have been shown to bind phosphatidylinositol-3, 4, 5-triphosphate (PtdIns(3,4,5)P3) [, , ].
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents the C2 domain of the Dock-D members. In addition to the C2 domain (also known as the DHR-1 domain) and the DHR-2, Dock-D members contain a functionally uncharacterised domain and a PH domain upstream of the C2 domain. DHR-2 has the catalytic activity for Rac and/or Cdc42, but is structurally unrelated to the DH domain. The C2/DHR-1 domains of Dock1 (also known as Dock180) and Dock4 have been shown to bind phosphatidylinositol-3, 4, 5-triphosphate (PtdIns(3,4,5)P3). The PH domain broadly binds to phospholipids and is thought to be involved in targeting the plasma membrane [, , ].
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents the C2 domain of the Dock-B members. Most of these members have been shown to be GEFs specific for Rac, although Dock4 has also been shown to interact indirectly with the Ras family GTPase Rap1, probably through Rap regulatory proteins. In addition to the C2 domain (also known as DHR-1 domain) and the DHR-2 domain, Dock-B members contain a SH3 domain upstream of the C2 domain and a proline-rich region downstream. DHR-2 has the catalytic activity for Rac and/or Cdc42, but is structurally unrelated to the DH domain. The C2/DHR-1 domains of Dock1 (also known as Dock180) and Dock4 have been shown to bind phosphatidylinositol-3, 4, 5-triphosphate (PtdIns(3,4,5)P3)[, , ].
This domain of unknown function is found in the Xeroderma pigmentosum group D (XPD) proteins which belong to a family of ATP-dependent helicases characterised by a 'D-E-A-H' motif. This resembles the'D-E-A-D-box' of other known helicases, which represents a special version of the B motif of ATP-binding proteins. In XPD,His replaces the second Asp. The DEAD box helicases are involved invarious aspects of RNA metabolism, including nuclear transcription, pre-mRNA splicing, ribosome biogenesis,nucleocytoplasmic transport, translation, RNA decay and organellar gene expression.
This entry represents the PX domain found in phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PI3K-C2beta). The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others []. PI3K-C2beta, the class II beta isoform of PI3K, contributes to the migration and survival of cancer cells []. It regulates Rac activity and impacts membrane ruffling, cell motility, and cadherin-mediated cell-cell adhesion [].The Phosphoinositide 3-Kinase (PI3K) family of enzymes catalyzes the phosphorylation of the 3-hydroxyl group of the inositol ring of phosphatidylinositol. 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 [, ]. PI3Ks are divided into three main classes (I, II, and III) based on their substrate specificity, regulation, and domain structure. Class II PI3Ks preferentially use PI as a substrate to produce PI3P, but can also phosphorylate PI4P to produce PI(3,4)P2. They function as monomers and do not associate with any regulatory subunits. Class II enzymes contain an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, an ATP-binding cataytic domain, a PX domain, and a second C2 domain at the C terminus [].
This entry represents the PX domain found in phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PI3K-C2alpha). The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others []. PI3K-C2alpha, the class II alpha isoform of PI3K, plays key roles in clathrin assembly and clathrin-mediated membrane trafficking, insulin signaling, vascular smooth muscle contraction, and the priming of neurosecretory granule exocytosis [, , ]. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction [, ].The Phosphoinositide 3-Kinase (PI3K) family of enzymes catalyzes the phosphorylation of the 3-hydroxyl group of the inositol ring of phosphatidylinositol. 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 [, ]. PI3Ks are divided into three main classes (I, II, and III) based on their substrate specificity, regulation, and domain structure. Class II PI3Ks preferentially use PI as a substrate to produce PI3P, but can also phosphorylate PI4P to produce PI(3,4)P2. They function as monomers and do not associate with any regulatory subunits. Class II enzymes contain an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, an ATP-binding cataytic domain, a PX domain, and a second C2 domain at the C terminus [].
This entry represents the C2 and GRAM domain-containing proteins from plants, including At1g03370 and At5g50170 from Arabidopsis. At1g03370 and At5g50170 contain two VASt domains, two C2 domains and a GRAM domain. Their function is not clear.
Synaptotagmin-like proteins (Slps) contain a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains, C2A and C2B []. The characteristic feature of the Slp family is the N-terminal domain (referred to as SHD for Slp Homology Domain), which is not found in other C-type tandem C2 proteins []. SHD functions as a specific Rab27A/B-binding domain []. This entry represents the C2B domain. The C2 domain is a Ca2+-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C and the protein kinase catalytic domain []. Regions with significant homology []to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding []and in membrane targetting processes such as subcellular localisation. The 3D structure of the C2 domain of synaptotagmin has been reported[], the domain forms an eight-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key []. Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca2+-binding loops are located at the end of an 8 stranded antiparallel β-sandwich.
Synaptotagmin-like proteins (Slps) contain a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains, C2A and C2B []. The characteristic feature of the Slp family is the N-terminal domain (referred to as SHD for Slp Homology Domain), which is not found in other C-type tandem C2 proteins []. SHD functions as a specific Rab27A/B-binding domain []. The C2B domain of Slp4 (also known as Granuphilin) interact with the plasma membrane lipid phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2][]. 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 beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including 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 andintersectin 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 is a family of short conserved proteins of 37 amino acids, described in Lactococcus phage c2 and in related phage. The function of these proteins is unknown.
This domain is found at the C terminus of phosphoribosyltransferases and phosphoribosyltransferase-like proteins. It contains putative transmembrane regions. It often appears together with calcium-ion dependent C2 domains ().
C. elegans Unc-13 is a phorbol ester/diacylglycerol-binding protein that plays a role in vesicle maturation during exocytosis [, ]. Unc-13 disruption causes diverse defects in the nervous system [, ]. Mammals contain three Unc-13 homologues: Unc-13 A, B and C (also known as Munc13-1/2/3) []. Unc13 homologue C is cerebellum-specific and regulates cerebellar synaptic transmission []. Homologues A and B are involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion []. They are essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses [].Unc-13 and its homologues contain both C1 and C2 domains. There are at least two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. The central C2 domain (C2B) is part of a C1-C2 tandem that functions in part to inhibit calcium-triggered neurotransmitter release. The C1 domain of Munc13 binds diacylglycerol (DAG) and beta phorbol esters (beta-PEs), while the neighbouring C2 domain (C2B) binds calcium and anionic phospholipids with a preference for both PI(4)P and PI(4,5)P2 []. This entry represents the second C2 domain, C2B, and has a type-II topology.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 beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including 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 [, , , , , , , ].
Las1 is an endoribonuclease responsible for cleavage at the C2 site during pre-rRNA processing []. It interacts with Grc3 polynucleotide kinase and is required for ribosome synthesis []. Las1-mediated C2 cleavage depends on the functional integrity of the associated Grc3 phosphotransferase, while phosphorylation of the 26S pre-rRNA by Grc3 relies on a functionally competent Las1 nuclease [, ].
A small family of bacterial proteins, found in several Bacteroides species. Structure determination (NMR and Xray) shows an immunoglobulin β-barrel fold. Multiple homologues have been found in human gut metagenomics data sets. Structural experimentation shows it to share features with two well-established protein architectures in the SCOP database, ie, C2 (calcium/lipid-binding domain) of the C2 domain ()and the PLAT/LH2 domain (). The C2 and PLAT/LH2 domains bind Ca2+ in their functions of targeting proteins to cell-membranes; this domain is also shown to bind Ca2+ as well as to be a novel fold [].
Cytosolic phospholipases A2 (cPLA2s) consist of a family of calcium-sensitive enzymes that function to generate lipid second messengers through hydrolysis of membrane-associated glycerophospholipids. In humans, the cPLA2 family contains six isoforms. Structural information of full length cPLA2alpha apo form, shows that it is composed of two domains; an N-terminal Ca2 + binding C2 domain and a C-terminal alpha/beta hydrolase core. This entry describes the N-terminal Ca2+ binding C2 domain which is composed of an eight-stranded antiparallel β-sandwich consisting of two four-stranded β-sheets. C2 domains are present in many lipid-binding proteins including Copines, CAPRI and Rabphilin-3A all of which are involved in membrane trafficking [].
Synaptotagmin-16 (SYT16) belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains. SYT16 is Ca(2+)-independent and may be involved in membrane trafficking in specific tissues outside the brain [].
This entry represents a domain of unknown function found in Eukaryotes. Many (but not all) proteins matched by this entry, such as the human protein Coiled-coil and C2 domain-containing protein 2A (), also contain and domains at the C-terminal region.
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 beta 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 [].
This entry represents a domain found in E3 ubiquitin-protein ligases HECW1 and HECW2 that lies upstream of the C2 domain. Its function is not clearly understood, but it might be to determine the substrate spectrum of the ligase [].
This superfamily represents the subdomain 1 found in the N-terminal domain of the protein dedicator of cytokinesis DOCK. Its function is unknown. The N-terminal domain is found between the variant SH3 domain and the C2 domain [].
This entry includes Rabphilin and Doc2. Rabphilin and Doc2s share highly homologous tandem C2 domains, although their N-terminal structures are completely different: Rabphilin contains an N-terminal Rab-binding domain (RBD), whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID) []. This entry also includes Noc2 (also known as Rabphilin-3A-like protein), which is a potential effector of Ras-associated binding proteins Rab3A and Rab27A. Noc2 contains an N-terminal Rab3A effector domain which harbors a conserved zinc finger, but lacks tandem C2 domains [].
The ferlin gene family are characterised by multiple tandem C2 domains and a C-terminal transmembrane domain. They are found in a wide range of species and their function remains unknown, however, mutations in its two most well-characterised members, dysferlin and otoferlin, have been implicated in human disease [].This domain is present in proteins of the Ferlin family, which includes Otoferlin, Myoferlin and Dysferlin. It is often located between two C2 domains [].
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 beta 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 matches the first C2 repeat in extendend synaptotagmins (the first and the third in E-Syt1), with a type-I topology [].
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 beta 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 [].
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 beta 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 [].
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 beta 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 [].
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 beta 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 [].
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 beta 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 [].
Tensins constitute an eukaryotic family of lipid phosphatases that are definedby the presence of two adjacent domains: a lipid phosphatase domain and aC2-like domain. The tensin-type C2 lacks the canonical Ca(2+) ligands found inclassical C2 domains, and in this respect it is similar tothe C2 domains of PKC-type [, ]. The tensin-type C2 domain can bindphospholipid membranes in a Ca(2+) independent manner []. In the tumorsuppressor protein PTEN, the best characterized member of the family, thelipid phosphatase domain was shown to specifically dephosphorylate the D3position of the inositol ring of the lipid second messenger,phosphatydilinositol-3-4-5-triphosphate (PIP3). The lipid phosphatase domaincontains the signature motif HCXXGXXR present in the active sites of proteintyrosine phosphatases (PTPs) and dual specificity phosphatases (DSPs).Furthermore, two invariant lysines are found only in the tensin-typephosphatase motif (HCKXGKXR) and are suspected to interact with the phosphategroup at position D1 and D5 of the inositol ring [, ].The crystal structure of the PTEN tumor suppressor has been solved []. The lipid phosphatase domain has a structure similar to thedual specificity phosphatase. However, PTEN has a largeractive site pocket that could be important to accomodate PI(3,4,5)P3. Thetensin-type C2 domain has a structure similar to the classical C2 domain thatmediates the Ca2+ dependent membrane recruitment of several signalingproteins. However the tensin-type C2 domain lacks two of the three conservedloops that bind Ca2+.Proteins known to contain a phosphatase and a C2 tensin-type domain are listed below:Tensin, a focal-adhesion molecule that binds to actin filaments. It may beinvolved in cell migration, cartilage development and in linking signaltransduction pathways to the cytoskeleton.Phosphatase and tensin homologue deleted on chromosome 10 protein (PTEN).It antagonizes PI 3-kinase signalling by dephosphorylating the 3-positionof the inositol ring of PI(3,4,5)P3 and thus inactivates downstreamsignalling. It plays major roles both during development and in the adultto control cell size, growth, and survival.Auxilin. It binds clathrin heavy chain and promotes its assembly intoregular cages.Cyclin G-associated kinase or auxilin-2. It is a potential regulator ofclathrin-mediated membrane trafficking.PTEN homologues in fungi have the tensin phosphatase domain, but they lack the C2 domain. .This entry represents the phosphatase domain.
This entry includes Synaptotagmin-14/14L/16 proteins. They belong to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains (known as C2A and C2B domains). The C2 domain is a Ca2-dependent membrane-targeting module. Most of the synaptotagmins have a unique N-terminal domain (transmembrane region) that is involved in membrane anchoring or specific ligand binding [].The 3D structure of the C2 domain of synaptotagmin has been reported []. The domain forms an eight-stranded beta sandwich constructed around a conserved 4-stranded motif, designated a C2 key []. Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca2-binding loops are located at the end of an 8 stranded antiparallel beta sandwich.In mammals Synaptotagmin-14 (SYT14) is expressed in brain (especially in the cerebellum) []. Mutations in SYT14 gene cause spinocerebellar ataxia, autosomal recessive, 11 (SCAR11), which is a clinically and genetically heterogeneous group of cerebellar disorders [].This entry also includes synaptotagmin-14-like protein (SYT14L, also known as sytdep) from human, which is highly expressed in mature peripheral blood neutrophils [].SYT16 is Ca2-independent and may be involved in membrane trafficking in specific tissues outside the brain [].
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 beta 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 [].
Synaptotagmins are synaptic vesicle membrane proteins found in abundance in nerve cells and some endocrine cells [, ]. The amino acid sequence of synaptotagmin comprises a single transmembrane region with a short vesicular N-terminal region, and a cytoplasmic C-terminal region containing 2 internal repeats similar to the C2 regulatory domain of protein kinase C. The protein is believed to be important in the docking and fusion of synaptic vesicles with the plasma membrane, i.e. with neurotransmitter release [, ].The 2 synaptotagmin C2 domains have been shown to have different functions: C2A binds phospholipid in a calcium-dependent manner, while C2B binds inositol polyphosphate and phospholipid irrespective of the presence of Ca2+[]. The structure of C2 domains in synaptotagmin I has been deduced: the C2 polypeptide forms an 8-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key []. The calcium binding region is a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif, while the site of phospholipid interaction is thought to be a polybasic sequence on the hairpin loop connecting strands 3 and 4 [].
Polyphosphate kinase (Ppk) catalyses the formation of polyphosphate from ATP, with chain lengths of up to a thousand or more orthophosphate molecules. This C1-terminal domain has a structure similar to phospholipase D. It is one of two closely related carboxy-terminal domains (C1 and C2 domains). Both the C1 and C2 domains (residues 322-502 and 503-687, respectively) consist of a sevenstranded mixed β-sheet flanked by five α-helices. However, the structural topology and relative orientations of the helices to the β-sheet in these two domains are different. The C1 and C2 domains are highly conserved in the PPK family. Some of the residues previously shown to be crucial for the enzyme catalytic activity are located in these two domains [].
Synaptotagmin-9 (SYT9) belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains (known as C2A and C2B domains). Most of the synaptotagmins have a unique N-terminal domain that is involved in membrane anchoring or specific ligand binding.Synaptotagmin 1 (originally called p65) was the first member of the synaptotagmin family identified [, ]. It has been shown to function as a Ca2+ sensor on the synaptic vesicle surface, therefore to regulate Ca2+ dependent neurotransmitter release [, ]. SYT9 shares high degree of protein sequence similarity with SYT1. However, unlike SYT1, the C2 domain of SYT9 does not form Ca2+/phospholipid complexes and the endogenous SYT9 does not associate with SNARE complexes in the absence or presence of Ca2+. The C2 domain of SYT9 has low Ca2+ affinity and may have a modulatory Ca2+-dependent function []. SYT9 is involved in endocrine secretion such as insulin release from large dense core vesicles in pancreatic beta-cells [].
Tricalbins constitute a synaptotagmin-like yeast protein family. Tricalbins contain several copies of C2 domains and are thought to be involved in membrane traffic [, , ]. 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 []. The family consists of three members: tricalbin 1-3. 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 [].
Ferlins are involved in vesicle fusion events []. Ferlins and other proteins, such as synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1).Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF [].
Polyphosphate kinase (Ppk) catalyses the formation of polyphosphate from ATP, with chain lengths of up to a thousand or more orthophosphate molecules. This C2-terminal domain has a structure similar to phospholipase D. It is one of two closely related carboxy-terminal domains (C1 and C2 domains). Both the C1 and C2 domains (residues 322-502 and 503-687, respectively) consist of a sevenstranded mixed β-sheet flanked by five α-helices. However, the structural topology and relative orientations of the helices to the β-sheet in these two domains are different. The C1 and C2 domains are highly conserved in the PPK family. Some of the residues previously shown to be crucial for the enzyme catalytic activity are located in these two domains [].
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) [].
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 [].
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 [].
The axin interaction dorsalization-associated (Aida) protein was characterised in zebrafish as a protein that utilizes its C-terminal region to interact with axis formation inhibitor (Axin), which is a microtubule-interacting scaffold protein for several distinct signalling proteins in the Wnt cascade. The C-terminal region of the Aida protein is a distinct version of the C2 domain. This Aida-type C2 domain is found in the C-terminal region of the proteins and it is critical for interactions with cytoskeletal in the context of cellular adhesion points, thus, it is combined with diverse domains related to cytoskeletal functions, e.g. EF hands, coiled coils, IQ calmodulin-binding motifs, ankyrin repeats and myosin head motor domain, or with a second lipid-binding domain, e.g. the PH domain. The Aida-type C2 domain is found only in the metazoan, choanoflagellate, chromist and chlorophyte lineages [, ].This domain has predominantly a β-strand globular fold composed of an antiparallel β-sandwich with two β-sheets, and three short α-helices to stabilize the conformation [].
This entry represents double C2-like domain-containing protein gamma (Doc2g). The Doc2 (double C2) family members Doc2a and Doc2b are characterised by an N-terminal Munc13-1 interacting domain, and two C2 domains that interact with Ca(2+) and phospholipid at the C terminus. In contrast, the C2 domains of Doc2g impair Ca(2+)-dependent phospholipid binding activity. The Ca2+-independent C2A domain of Doc2g seems to have a nuclear localisation function []. Doc2g may also function as an effector for Munc13-1, and it may be involved in the regulation of vesicular trafficking [].
The MD-2-related lipid-recognition (ML) domain is implicated in lipid recognition, particularly in the recognition of pathogen related products. It has an immunoglobulin-likeβ-sandwich fold similar to that of E-set Ig domains. This domain is present in proteins from plants, animals and fungi, including the following proteins:Epididymal secretory protein E1 (also known as Niemann-Pick C2 protein - Npc2), which is known to bind cholesterol. Niemann-Pick disease type C2 is a fatal hereditary disease characterised by accumulation of low-density lipoprotein-derived cholesterol in lysosomes [].House-dust mite allergen proteins such as Der f 2 from Dermatophagoides farinae and Der p 2 from Dermatophagoides pteronyssinus [].
In humans, Rabphilin-3A (RPH3A) contains two C2 domains and one RabBD (Rab-binding) domain. RPH3A may interact with the SNARE complex and regulate synaptic vesicle exocytosis and Ca2+-triggered neurotransmitter release []. It has been linked to neurodegenerative diseases, such as Huntington's disease [], Lewy body disease []and Alzheimer's disease [].
Synaptotagmin-like protein 5 (SYTL5, also known as Slp5) belongs to the synaptotagmin-like protein family, which contains a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains. Slp5 interacts with the GTP-bound form of Rab27A both in vitro and in intact cells. It is highly expressed in human placenta and liver. It may be involved in Rab27A-dependent membrane trafficking in specific tissues [].
Synaptotagmin-like protein 3 (SYTL3, also known as Slp3) belongs to the synaptotagmin-like protein family, which contains a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains. Slp3 binds phospholipids in the presence of calcium ions []. In mouse cytotoxic T lymphocytes, Slp3 is an effector of Rab27a and interacts with kinesin-1 through the tetratricopeptide repeat of the kinesin-1 light chain [].
Synaptotagmin-10 (SYT10) belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains. Most of the synaptotagmins have a unique N-terminal domain that is involved in membrane anchoring or specific ligand binding. SYT10 localises to olfactory bulb and controls the Ca(2+)-dependent exocytosis that is spatially and temporally distinct from Ca(2+)-dependent synaptic vesicle exocytosis controlled by SYT1 [].
This entry includes the serine endopeptidase complement C1s subcomponent (MEROPS identifier S01.193). C1s has trypsin-like specificity and activates the precursors of complement components C2 and C4 [, ]. It is inhibited by C1 inhibitor []. C1s is calcium-dependent and in the golden hamster is known as calcium-dependent serine proteinase.
This group represents 3-ketoacyl-CoA synthases (KCSs) from plants [, ]. They are also known as very long-chain fatty acid (VLCFA) condensing enzymes, and they catalyse the first committed step during the fatty acid elongation process, which is the condensation of C2 units to acyl-CoA. Arabidopsis contains 21 KCS members [].
The ferlin gene family are characterised by multiple tandem C2 domains and a C-terminal transmembrane domain. They are found in a wide range of species and their function remains unknown, however, mutations in its two most well-characterised members, dysferlin and otoferlin, have been implicated in human disease [].This is central domain B in proteins of the Ferlin family [].
The ferlin gene family are characterised by multiple tandem C2 domains and a C-terminal transmembrane domain. They are found in a wide range of species and their function remains unknown, however, mutations in its two most well-characterised members, dysferlin and otoferlin, have been implicated in human disease [].This is central domain A in proteins of the Ferlin family [].
The enzyme in this family is involved in the C2 methylation of bacterial hopanoids. Although the reaction is shown with methylcobalamin acting as the methyl donor, it is possible that SAM might be the methyl donor for the reaction (because this is another function of the SAM cofactor) [].
This domain is found near to the N terminus of some dedicator of cytokinesis (DOCK) proteins, between the variant SH3 domain and the C2 domain []. This is an α-helical region that mediates interactions with ELMO subunits and provides a major site for interactions between the SH3 and ARM domains of these proteins [].
The mycobacterial members of this family are expressed from part of the ergothioneine biosynthetic gene cluster. EGTD is the histidine methyltransferase that transfers three methyl groups to the alpha-amino moiety of histidine, in the first stage of the production of this histidine betaine derivative that carries a thiol group attached to the C2 atom of an imidazole ring [].
This entry includes INPP4A and INPP4B. They are inositol lipid 4-phosphatases that hydrolyze PtdIns(3,4)P2, a phosphoinositide generated by PI3K signaling [, ]. They contain a C2 domain in their N termini and a phosphatase domain at their C termini. INPP4A is a suppressor of glutamate excitotoxicity in the central nervous system [], while INPP4B acts as a tumour suppressor [].
