C2 domain of Perforin; Perforin contains a single copy of a C2 domain in its C-terminus and plays a role in lymphocyte-mediated cytotoxicity. Mutations in perforin leads to familial hemophagocytic lymphohistiocytosis type 2. The function of perforin is calcium dependent and the C2 domain is thought to confer this binding to target cell membranes. C2 domains fold into an 8-standed beta-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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621 388 SPRDPCQCVCHGSAVTTQDCCPRQRGLAQLEVTFIQAWGLWGDWFTATDAYVKLFFGGQELRTSTVWDNNNPIWSVRLDF 467
Cdd:cd04032    1 SARDNCPCVCSSSPNVNSNCCPTRRGLATLTVTVLRATGLWGDYFTSTDGYVKVFFGGQEKRTEVIWNNNNPRWNATFDF 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 133908621 468 GDVLLATGGPLRLQVWDQDSGRDDDLLGTCDQAPKSGSHEVRCNLNH 514
Cdd:cd04032   81 GSVELSPGGKLRFEVWDRDNGWDDDLLGTCSVVPEAGVHEDSCQLNH 127

C2 domain of Perforin; Perforin contains a single copy of a C2 domain in its C-terminus and plays a role in lymphocyte-mediated cytotoxicity. Mutations in perforin leads to familial hemophagocytic lymphohistiocytosis type 2. The function of perforin is calcium dependent and the C2 domain is thought to confer this binding to target cell membranes. C2 domains fold into an 8-standed beta-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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621 388 SPRDPCQCVCHGSAVTTQDCCPRQRGLAQLEVTFIQAWGLWGDWFTATDAYVKLFFGGQELRTSTVWDNNNPIWSVRLDF 467
Cdd:cd04032    1 SARDNCPCVCSSSPNVNSNCCPTRRGLATLTVTVLRATGLWGDYFTSTDGYVKVFFGGQEKRTEVIWNNNNPRWNATFDF 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 133908621 468 GDVLLATGGPLRLQVWDQDSGRDDDLLGTCDQAPKSGSHEVRCNLNH 514
Cdd:cd04032   81 GSVELSPGGKLRFEVWDRDNGWDDDLLGTCSVVPEAGVHEDSCQLNH 127

MAC/Perforin domain; The membrane-attack complex (MAC) of the complement system forms transmembrane channels. These channels disrupt the phospholipid bilayer of target cells, leading to cell lysis and death. A number of proteins participate in the assembly of the MAC. Freshly activated C5b binds to C6 to form a C5b-6 complex, then to C7 forming the C5b-7 complex. The C5b-7 complex binds to C8, which is composed of three chains (alpha, beta, and gamma), thus forming the C5b-8 complex. C5b-8 subsequently binds to C9 and acts as a catalyst in the polymerization of C9. Active MAC has a subunit composition of C5b-C6-C7-C8-C9{n}. Perforin is a protein found in cytolytic T-cell and killer cells. In the presence of calcium, perforin polymerizes into transmembrane tubules and is capable of lysing, non-specifically, a variety of target cells. There are a number of regions of similarity in the sequences of complement components C6, C7, C8-alpha, C8-beta, C9 and perforin. The X-ray crystal structure of a MACPF domain reveals that it shares a common fold with bacterial cholesterol dependent cytolysins (pfam01289) such as perfringolysin O. Three key pieces of evidence suggests that MACPF domains and CDCs are homologous: Functional similarity (pore formation), conservation of three glycine residues at a hinge in both families and conservation of a complex core fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621  149 GSHSQAANFA--AQKTHQDQYSFSTDTVECRFYSFHVV--HTPPLHPDFKRALGDLPHHFNASTQPAYLRLISNYGTHFI 224
Cdd:pfam01823   1 GSFSASSEFKkmSDKSKQKKKSLIISKSTCSLYQFTLKrsNKLQLSDEFLQALSDLPDNYDYAAKATYIQFFDKYGTHYI 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621  225 RAVELGGRISALTALRTCELALEGLTDNEVEDCLTVEAQVNIGihgsiSAEAKACEEKKKKHKMTASFHQTYRERHSEVV 304
Cdd:pfam01823  81 TSVTLGGKIVYVLKLDKSQLEDLKLKGEDVKICLSASAGASIG-----SVNLKGCSKNSSSTKEKKSFNQEIESSITLVI 155

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 133908621  305 GGhhtsindLLFGIQAGPEQYSAWVNSLPGSPGLVDYTLEPLHVLLDSQDPRREALRRALSQY 367
Cdd:pfam01823 156 GG-------TPESIDDDSKTYSDWAESVKDNPMPIDFELTPISELLKGVPLKKENLRKALEEY 211

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621  416 QLEVTFIQAWGL-WGDWFTATDAYVKLFF--GGQELRTSTVWDNNNPIWSVRLDFgDVLLATGGPLRLQVWDQDSGRDDD 492
Cdd:pfam00168   2 RLTVTVIEAKNLpPKDGNGTSDPYVKVYLldGKQKKKTKVVKNTLNPVWNETFTF-SVPDPENAVLEIEVYDYDRFGRDD 80

                  ....*
gi 133908621  493 LLGTC 497
Cdd:pfam00168  81 FIGEV 85

Ca2+-dependent lipid-binding protein, contains C2 domain [General function prediction only];

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 133908621  436 DAYVKLFFGGQELRTS-TVWDNNNPIWSVRLDFgDVLLATGGPLRLQVWDQDSGRDDDLLGTCDQAPKSGSHEVRCNLN 513
Cdd:COG5038  1062 DPFVKLFLNEKSVYKTkVVKKTLNPVWNEEFTI-EVLNRVKDVLTINVNDWDSGEKNDLLGTAEIDLSKLEPGGTTNSN 1139

C2 domain of Perforin; Perforin contains a single copy of a C2 domain in its C-terminus and plays a role in lymphocyte-mediated cytotoxicity. Mutations in perforin leads to familial hemophagocytic lymphohistiocytosis type 2. The function of perforin is calcium dependent and the C2 domain is thought to confer this binding to target cell membranes. C2 domains fold into an 8-standed beta-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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621 388 SPRDPCQCVCHGSAVTTQDCCPRQRGLAQLEVTFIQAWGLWGDWFTATDAYVKLFFGGQELRTSTVWDNNNPIWSVRLDF 467
Cdd:cd04032    1 SARDNCPCVCSSSPNVNSNCCPTRRGLATLTVTVLRATGLWGDYFTSTDGYVKVFFGGQEKRTEVIWNNNNPRWNATFDF 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 133908621 468 GDVLLATGGPLRLQVWDQDSGRDDDLLGTCDQAPKSGSHEVRCNLNH 514
Cdd:cd04032   81 GSVELSPGGKLRFEVWDRDNGWDDDLLGTCSVVPEAGVHEDSCQLNH 127

MAC/Perforin domain; The membrane-attack complex (MAC) of the complement system forms transmembrane channels. These channels disrupt the phospholipid bilayer of target cells, leading to cell lysis and death. A number of proteins participate in the assembly of the MAC. Freshly activated C5b binds to C6 to form a C5b-6 complex, then to C7 forming the C5b-7 complex. The C5b-7 complex binds to C8, which is composed of three chains (alpha, beta, and gamma), thus forming the C5b-8 complex. C5b-8 subsequently binds to C9 and acts as a catalyst in the polymerization of C9. Active MAC has a subunit composition of C5b-C6-C7-C8-C9{n}. Perforin is a protein found in cytolytic T-cell and killer cells. In the presence of calcium, perforin polymerizes into transmembrane tubules and is capable of lysing, non-specifically, a variety of target cells. There are a number of regions of similarity in the sequences of complement components C6, C7, C8-alpha, C8-beta, C9 and perforin. The X-ray crystal structure of a MACPF domain reveals that it shares a common fold with bacterial cholesterol dependent cytolysins (pfam01289) such as perfringolysin O. Three key pieces of evidence suggests that MACPF domains and CDCs are homologous: Functional similarity (pore formation), conservation of three glycine residues at a hinge in both families and conservation of a complex core fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621  149 GSHSQAANFA--AQKTHQDQYSFSTDTVECRFYSFHVV--HTPPLHPDFKRALGDLPHHFNASTQPAYLRLISNYGTHFI 224
Cdd:pfam01823   1 GSFSASSEFKkmSDKSKQKKKSLIISKSTCSLYQFTLKrsNKLQLSDEFLQALSDLPDNYDYAAKATYIQFFDKYGTHYI 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621  225 RAVELGGRISALTALRTCELALEGLTDNEVEDCLTVEAQVNIGihgsiSAEAKACEEKKKKHKMTASFHQTYRERHSEVV 304
Cdd:pfam01823  81 TSVTLGGKIVYVLKLDKSQLEDLKLKGEDVKICLSASAGASIG-----SVNLKGCSKNSSSTKEKKSFNQEIESSITLVI 155

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 133908621  305 GGhhtsindLLFGIQAGPEQYSAWVNSLPGSPGLVDYTLEPLHVLLDSQDPRREALRRALSQY 367
Cdd:pfam01823 156 GG-------TPESIDDDSKTYSDWAESVKDNPMPIDFELTPISELLKGVPLKKENLRKALEEY 211

Protein kinase C conserved region 2 (CalB); Ca2+-binding motif present in phospholipases, protein kinases C, and synaptotagmins (among others). Some do not appear to contain Ca2+-binding sites. Particular C2s appear to bind phospholipids, inositol polyphosphates, and intracellular proteins. Unusual occurrence in perforin. Synaptotagmin and PLC C2s are permuted in sequence with respect to N- and C-terminal beta strands. SMART detects C2 domains using one or both of two profiles.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621   416 QLEVTFIQAWGL-WGDWFTATDAYVKLFFGGQEL---RTSTVWDNNNPIWSVRLDFgDVLLATGGPLRLQVWDQDSGRDD 491
Cdd:smart00239   1 TLTVKIISARNLpPKDKGGKSDPYVKVSLDGDPKekkKTKVVKNTLNPVWNETFEF-EVPPPELAELEIEVYDKDRFGRD 79

                   ....*.
gi 133908621   492 DLLGTC 497
Cdd:smart00239  80 DFIGQV 85

C2 domain second repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); MCTPs are involved in Ca2+ signaling at the membrane. MCTP is composed of a variable N-terminal sequence, three C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-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 cd contains the second C2 repeat, C2B, and has a type-II topology.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621 419 VTFIQAWGL-WGDWFTATDAYVKLFFGGQELRTSTVWDNNNPIWSVRLDFgDVLLATGGPLRLQVWDQDSGRDDDLLGTC 497
Cdd:cd08376    4 IVLVEGKNLpPMDDNGLSDPYVKFRLGNEKYKSKVCSKTLNPQWLEQFDL-HLFDDQSQILEIEVWDKDTGKKDEFIGRC 82

                         90       100
                 ....*....|....*....|..
gi 133908621 498 D----QAPKSGSHEVRCNLNHG 515
Cdd:cd08376   83 EidlsALPREQTHSLELELEDG 104

C2 domain present in Arf GTPase Activating Proteins (GAP); ArfGAP is a GTPase activating protein which regulates the ADP ribosylation factor Arf, a member of the Ras superfamily of GTP-binding proteins. The GTP-bound form of Arf is involved in Golgi morphology and is involved in recruiting coat proteins. ArfGAP is responsible for the GDP-bound form of Arf which is necessary for uncoating the membrane and allowing the Golgi to fuse with an acceptor compartment. These proteins contain an N-terminal ArfGAP domain containing the characteristic zinc finger motif (Cys-x2-Cys-x(16,17)-x2-Cys) and C-terminal C2 domain. C2 domains were first identified in Protein Kinase C (PKC). C2 domains fold into an 8-standed beta-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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 133908621 432 FTATDAYVKLFFGGQELRTSTVWDNNNPIWSVRLDFGdvLLATGGPLRLQVWDQDSGRDDDLLG 495
Cdd:cd04038   19 FTSSDPYVVLTLGNQKVKTRVIKKNLNPVWNEELTLS--VPNPMAPLKLEVFDKDTFSKDDSMG 80

C2 domain first repeat present in Synaptotagmin-like proteins; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-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 cd contains the first C2 repeat, C2A, and has a type-I topology.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621 436 DAYVKLFFGGQELRTSTVWDNNNPIWSVRLDFgDVLLATGGPLRLQVWDQDSGRDDDLLG 495
Cdd:cd04024   25 DPYAILSVGAQRFKTQTIPNTLNPKWNYWCEF-PIFSAQNQLLKLILWDKDRFAGKDYLG 83

C2 domain present in the putative elicitor-responsive gene; In plants elicitor-responsive proteins are triggered in response to specific elicitor molecules such as glycolproteins, peptides, carbohydrates and lipids. A host of defensive responses are also triggered resulting in localized cell death. Antimicrobial secondary metabolites, such as phytoalexins, or defense-related proteins, including pathogenesis-related (PR) proteins are also produced. There is a single C2 domain present here. C2 domains fold into an 8-standed beta-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. Members have a type-II topology.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621 417 LEVTFIQAWGLWG-DWFTATDAYVKLFFGGQElRTSTVW--DNNNPIWSVRLDFgDVLLATGGP---LRLQVWDQDSGRD 490
Cdd:cd04049    3 LEVLLISAKGLQDtDFLGKIDPYVIIQCRTQE-RKSKVAkgDGRNPEWNEKFKF-TVEYPGWGGdtkLILRIMDKDNFSD 80

                 ....*
gi 133908621 491 DDLLG 495
Cdd:cd04049   81 DDFIG 85

C2 domain first and third repeat in Synaptotagmin-like proteins; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-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 cd contains either the first or third repeat in Synaptotagmin-like proteins with a type-I topology.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 133908621 436 DAYVKLFFGGQELRTSTVWDNNNPIWSvrlDFGDVLL--ATGGPLRLQVWDQDSGrDDDLLGTCD 498
Cdd:cd08391   29 DPYVIVRVGAQTFKSKVIKENLNPKWN---EVYEAVVdeVPGQELEIELFDEDPD-KDDFLGRLS 89

C2 domain first repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); plant subset; MCTPs are involved in Ca2+ signaling at the membrane. Plant-MCTPs are composed of a variable N-terminal sequence, four C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-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 cd contains the first C2 repeat, C2A, and has a type-II topology.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 133908621 437 AYVKLFFGGQELRTSTVWDNNNPIWSVRLDF--GDVLLATGGPLRLQVW-DQDSGRDDDLLG 495
Cdd:cd04022   23 AYVELDFDGQKKRTRTKPKDLNPVWNEKLVFnvSDPSRLSNLVLEVYVYnDRRSGRRRSFLG 84

C2 domain in Munc13 (mammalian uncoordinated) proteins; fungal group; C2-like domains are thought to be involved in phospholipid binding in a Ca2+ independent manner in both Unc13 and Munc13. Caenorabditis elegans Unc13 has a central domain with sequence similarity to PKC, which includes C1 and C2-related domains. Unc13 binds phorbol esters and DAG with high affinity in a phospholipid manner. Mutations in Unc13 results in abnormal neuronal connections and impairment in cholinergic neurotransmission in the nematode. Munc13 is the mammalian homolog which are expressed in the brain. There are 3 isoforms (Munc13-1, -2, -3) and are thought to play a role in neurotransmitter release and are hypothesized to be high-affinity receptors for phorbol esters. Unc13 and Munc13 contain both C1 and C2 domains. There are two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. Munc13 interacts with syntaxin, synaptobrevin, and synaptotagmin suggesting a role for these as scaffolding proteins. C2 domains fold into an 8-standed beta-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 cd contains the second C2 repeat, C2B, and has a type-II topology.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 133908621 436 DAYVKLF--FGGQEL-RTSTVWDNNNPIWS----VRLDFGDVLLatggpLRLQVWDQDSGRDDDLLGTC 497
Cdd:cd04043   23 DPYVTLVdtNGKRRIaKTRTIYDTLNPRWDeefeLEVPAGEPLW-----ISATVWDRSFVGKHDLCGRA 86

C2 domain first repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); MCTPs are involved in Ca2+ signaling at the membrane. MCTP is composed of a variable N-terminal sequence, three C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-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 cd contains the first C2 repeat, C2A, and has a type-II topology.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 133908621 430 DWFTATDAYVKLFFGGQEL-RTSTVWDNNNPIW----SVRLDfgDVLlatgGPLRLQVWDQDSGRDDDLLGTC 497
Cdd:cd04042   16 DRGGTSDPYVKFKYGGKTVyKSKTIYKNLNPVWdekfTLPIE--DVT----QPLYIKVFDYDRGLTDDFMGSA 82

C2 domain second repeat in Munc13 (mammalian uncoordinated) proteins; C2-like domains are thought to be involved in phospholipid binding in a Ca2+ independent manner in both Unc13 and Munc13. Caenorabditis elegans Unc13 has a central domain with sequence similarity to PKC, which includes C1 and C2-related domains. Unc13 binds phorbol esters and DAG with high affinity in a phospholipid manner. Mutations in Unc13 results in abnormal neuronal connections and impairment in cholinergic neurotransmission in the nematode. Munc13 is the mammalian homolog which are expressed in the brain. There are 3 isoforms (Munc13-1, -2, -3) and are thought to play a role in neurotransmitter release and are hypothesized to be high-affinity receptors for phorbol esters. Unc13 and Munc13 contain both C1 and C2 domains. There are two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. Munc13 interacts with syntaxin, synaptobrevin, and synaptotagmin suggesting a role for these as scaffolding proteins. C2 domains fold into an 8-standed beta-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 cd contains the second C2 repeat, C2B, and has a type-II topology.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621 415 AQLEVTFIQAWGLWGDWFTAT-DAYVKLFFGGQELRTSTVWDNNNPIWSVRLDFGdvLLATGGPLRLQVWDQdsgrDDDL 493
Cdd:cd04027    1 AKISITVVCAQGLIAKDKTGTsDPYVTVQVGKTKKRTKTIPQNLNPVWNEKFHFE--CHNSSDRIKVRVWDE----DDDI 74

C2 domain fourth repeat in Ferlin; 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 beta-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 cd contains the fourth C2 repeat, C2D, and has a type-II topology.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 133908621 436 DAYVKLFFGGQELRTSTVWDNNNPIWSVRLDFGDVLLAtGGP---------LRLQVWDQDSGRDDDLLGTC 497
Cdd:cd04017   23 DPFARVSFLNQSQETEVIKETLSPTWDQTLIFDEVELY-GSPeeiaqnpplVVVELFDQDSVGKDEFLGRS 92

C2 domain fourth repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-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 cd contains the fifth C2 repeat, C2E, and has a type-II topology.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 133908621 436 DAYVKLFFGGQEL-RTSTVWDNNNPIWSVRLDFgDVLLATGGPLRLQVWDQDSGRDDDLLGTC 497
Cdd:cd04040   21 DPFVKFYLNGEKVfKTKTIKKTLNPVWNESFEV-PVPSRVRAVLKVEVYDWDRGGKDDLLGSA 82

C2 domain present in Phosphoinositide-specific phospholipases C (PLC); PLCs are involved in the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) to d-myo-inositol-1,4,5-trisphosphate (1,4,5-IP3) and sn-1,2-diacylglycerol (DAG). 1,4,5-IP3 and DAG are second messengers in eukaryotic signal transduction cascades. PLC is composed of a N-terminal PH domain followed by a series of EF hands, a catalytic TIM barrel and a C-terminal C2 domain. C2 domains fold into an 8-standed beta-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. Members here have a type-II topology.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 133908621 438 YVKL-FFG-----GQELRTSTVWDNN-NPIWSVRLDFgDVL---LATggpLRLQVWDQDSGrDDDLLGTC 497
Cdd:cd00275   28 YVEVeIHGlpaddSAKFKTKVVKNNGfNPVWNETFEF-DVTvpeLAF---LRFVVYDEDSG-DDDFLGQA 92