C2 domain; The C2 domain was first identified in 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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  12 LEVTVVGCQKLKDTEWFSRQDPYVVLEYGG-RSHRTRTCTDgGKNAVFQEKFIFTLIEGLRD-LKVAVWNSNTLSTDDFI 89
Cdd:cd00030   1 LRVTVIEARNLPAKDLNGKSDPYVKVSLGGkQKFKTKVVKN-TLNPVWNETFEFPVLDPESDtLTVEVWDKDRFSKDDFL 79

                        90       100
                ....*....|....*....|
gi 18418388  90 GNATIQLQKVLSQEYDDCTW 109
Cdd:cd00030  80 GEVEIPLSELLDSGKEGELW 99

C2 domain; The C2 domain was first identified in 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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  12 LEVTVVGCQKLKDTEWFSRQDPYVVLEYGG-RSHRTRTCTDgGKNAVFQEKFIFTLIEGLRD-LKVAVWNSNTLSTDDFI 89
Cdd:cd00030   1 LRVTVIEARNLPAKDLNGKSDPYVKVSLGGkQKFKTKVVKN-TLNPVWNETFEFPVLDPESDtLTVEVWDKDRFSKDDFL 79

                        90       100
                ....*....|....*....|
gi 18418388  90 GNATIQLQKVLSQEYDDCTW 109
Cdd:cd00030  80 GEVEIPLSELLDSGKEGELW 99

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 18418388     11 ILEVTVVGCQKLKDTEWFSRQDPYVVLEYGG---RSHRTRTCTDGGkNAVFQEKFIFTLIE-GLRDLKVAVWNSNTLSTD 86
Cdd:smart00239   1 TLTVKIISARNLPPKDKGGKSDPYVKVSLDGdpkEKKKTKVVKNTL-NPVWNETFEFEVPPpELAELEIEVYDKDRFGRD 79

                           90       100
                   ....*....|....*....|
gi 18418388     87 DFIGNATIQLQKVLSQEYDD 106
Cdd:smart00239  80 DFIGQVTIPLSDLLLGGRHE 99

C2 domain; The C2 domain was first identified in 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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  12 LEVTVVGCQKLKDTEWFSRQDPYVVLEYGG-RSHRTRTCTDgGKNAVFQEKFIFTLIEGLRD-LKVAVWNSNTLSTDDFI 89
Cdd:cd00030   1 LRVTVIEARNLPAKDLNGKSDPYVKVSLGGkQKFKTKVVKN-TLNPVWNETFEFPVLDPESDtLTVEVWDKDRFSKDDFL 79

                        90       100
                ....*....|....*....|
gi 18418388  90 GNATIQLQKVLSQEYDDCTW 109
Cdd:cd00030  80 GEVEIPLSELLDSGKEGELW 99

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 18418388     11 ILEVTVVGCQKLKDTEWFSRQDPYVVLEYGG---RSHRTRTCTDGGkNAVFQEKFIFTLIE-GLRDLKVAVWNSNTLSTD 86
Cdd:smart00239   1 TLTVKIISARNLPPKDKGGKSDPYVKVSLDGdpkEKKKTKVVKNTL-NPVWNETFEFEVPPpELAELEIEVYDKDRFGRD 79

                           90       100
                   ....*....|....*....|
gi 18418388     87 DFIGNATIQLQKVLSQEYDD 106
Cdd:smart00239  80 DFIGQVTIPLSDLLLGGRHE 99

C2 domain found in fungal Ingression 1 (Inn1) proteins; 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 other proteins 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. It has been shown that the C2 domain of human synaptotagmin induces curvature in target membranes and thereby contributes to fusion of these membranes with synaptic vesicles. The C2 domain was first identified in 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 synaptotagmin1. 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 18418388  11 ILEVTVVGCQKLKDTEWFSRQDPYVVLEYGGRSHRTRTCTDGGKNAVFQEKFIFTLIE-GLRDLKVAVWNsNTLSTDDFI 89
Cdd:cd08681   2 TLVVVVLKARNLPNKRKLDKQDPYCVLRIGGVTKKTKTDFRGGQHPEWDEELRFEITEdKKPILKVAVFD-DDKRKPDLI 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 18418388  90 GNATIQLQKVLsQEYDDCTW-TLQSKtGRFAGEVQLLLHY 128
Cdd:cd08681  81 GDTEVDLSPAL-KEGEFDDWyELTLK-GRYAGEVYLELTF 118

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  10 QILEVTVVGCQKLKDTEWFSRQ--DPYVVLE-YG-----GRSHRTRTCTDGGKNAVFQEKFIFTLIEG-LRDLKVAVWNS 80
Cdd:cd00275   2 LTLTIKIISGQQLPKPKGDKGSivDPYVEVEiHGlpaddSAKFKTKVVKNNGFNPVWNETFEFDVTVPeLAFLRFVVYDE 81

                        90
                ....*....|....
gi 18418388  81 NTlSTDDFIGNATI 94
Cdd:cd00275  82 DS-GDDDFLGQACL 94

C2 domain first 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 first C2 repeat, C2A, and has a type-II topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  11 ILEVTVVGCQKLKDTEWFSRQ-DPYVVLEYGGRSH--RTRTCTDgGKNAVFQEKfIFTLIEGLRD-LKVAVWNSNTLSTD 86
Cdd:cd04044   3 VLAVTIKSARGLKGSDIIGGTvDPYVTFSISNRRElaRTKVKKD-TSNPVWNET-KYILVNSLTEpLNLTVYDFNDKRKD 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 18418388  87 DFIGNATIQLQKVLSQ-EYDDCTWTLQSKtGRFAGEVQLLLHY 128
Cdd:cd04044  81 KLIGTAEFDLSSLLQNpEQENLTKNLLRN-GKPVGELNYDLRF 122

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  12 LEVTVVGCQKLKDTEWFSRQDPYVVLEYGGRSHRTRTcTDGGKNAVFQEKFIFTLIEGLRDLKVAVWNSN---------- 81
Cdd:cd04027   3 ISITVVCAQGLIAKDKTGTSDPYVTVQVGKTKKRTKT-IPQNLNPVWNEKFHFECHNSSDRIKVRVWDEDddiksrlkqk 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 18418388  82 -TLSTDDFIGNATIQLqKVLSQEYDdcTW-TLQSKTGRFAGEVQLLLH 127
Cdd:cd04027  82 fTRESDDFLGQTIIEV-RTLSGEMD--VWyNLEKRTDKSAVSGAIRLH 126

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388    2 SMMAGIQGQ---ILEVTVVGCQKLKDTEWFSRQ--DPYVVLEYGGRSH-RTRTCTDGGkNAVFQEKFiFTLIEGLRD-LK 74
Cdd:COG5038  425 QIMAGDSGTaigVVEVKIKSAEGLKKSDSTINGtvDPYITVTFSDRVIgKTRVKKNTL-NPVWNETF-YILLNSFTDpLN 502

                         90       100       110
                 ....*....|....*....|....*....|
gi 18418388   75 VAVWNSNTLSTDDFIGNATIQLQKVLSQEY 104
Cdd:COG5038  503 LSLYDFNSFKSDKVVGSTQLDLALLHQNPV 532

C2 domain present in Toll-interacting protein (Tollip); 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. There is a single C2 domain present in Tollip. 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 18418388  12 LEVTVVGCqKLKDTEWFSRQDPYVVLEYGGRSHRTRTCTDGGKNAVFQEKFIFTLIEGLRDLKVAVWNSNTLSTDDFIGN 91
Cdd:cd04016   4 LSITVVQA-KLVKNYGLTRMDPYCRIRVGHAVYETPTAYNGAKNPRWNKTIQCTLPEGVDSIYIEIFDERAFTMDERIAW 82

                        90       100
                ....*....|....*....|....*.
gi 18418388  92 ATIQL-QKVLSQEYDDCTWTLQSKTG 116
Cdd:cd04016  83 THITIpESVFNGETLDDWYSLSGKQG 108

C2 domain fifth 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 fifth C2 repeat, C2E, and has a type-II topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  32 DPYVVLEYGGRSHRTR-TCTDGGKNAVFQEKFIF-TLIEGLRDLKVAVWNSNTLSTDDFIGNATIQL----------QKV 99
Cdd:cd04037  22 DPYLKIKLGKKKINDRdNYIPNTLNPVFGKMFELeATLPGNSILKISVMDYDLLGSDDLIGETVIDLedrffskhraTCG 101

                ....*
gi 18418388 100 LSQEY 104
Cdd:cd04037 102 LPPTY 106

C2 domain first repeat contained in Rab3-interacting molecule (RIM) proteins; RIMs are believed to organize specialized sites of the plasma membrane called active zones. They also play a role in controlling neurotransmitter release, plasticity processes, as well as memory and learning. RIM contains an N-terminal zinc finger domain, a PDZ domain, and two C-terminal C2 domains (C2A, C2B). 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-I topology and do not bind Ca2+.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388   7 IQGQILEVTVVGCQKLKDTEWFSRQDPYV-VLEYGGRSH----RTRTCtDGGKNAVFQEKFIF------TLIEglRDLKV 75
Cdd:cd04031  13 KVTSQLIVTVLQARDLPPRDDGSLRNPYVkVYLLPDRSEkskrRTKTV-KKTLNPEWNQTFEYsnvrreTLKE--RTLEV 89

                        90       100
                ....*....|....*....|....*
gi 18418388  76 AVWNSNTLSTDDFIGNATIQLQKVL 100
Cdd:cd04031  90 TVWDYDRDGENDFLGEVVIDLADAL 114

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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  32 DPYVVLEYGGRSHRTRTCTDgGKNAVFQEKF--IFTLIEGLrDLKVAVWNSNTlSTDDFIGNATIQLQKVLSQEYDDcTW 109
Cdd:cd08391  29 DPYVIVRVGAQTFKSKVIKE-NLNPKWNEVYeaVVDEVPGQ-ELEIELFDEDP-DKDDFLGRLSIDLGSVEKKGFID-EW 104

                        90
                ....*....|
gi 18418388 110 -TLQS-KTGR 117
Cdd:cd08391 105 lPLEDvKSGR 114

C2 domain second repeat of Ras GTPase activating proteins (GAPs); RasGAPs suppress Ras function by enhancing the GTPase activity of Ras proteins resulting in the inactive GDP-bound form of Ras. In this way it can control cellular proliferation and differentiation. The proteins here all contain two tandem C2 domains, a Ras-GAP domain, and a pleckstrin homology (PH)-like 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-I topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  32 DPYVVLEYGGRSH--------RTRTCtdggkNAVFQEKFIFTLIEG----------------LRDLKVAVWNSNTLSTDD 87
Cdd:cd08675  20 DPFARVTLNYSSKtdtkrtkvKKKTN-----NPRFDEAFYFELTIGfsyekksfkveeedleKSELRVELWHASMVSGDD 94

                        90
                ....*....|....*
gi 18418388  88 FIGNATIQLQKVLSQ 102
Cdd:cd08675  95 FLGEVRIPLQGLQQA 109

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 18418388  32 DPYVVLEYGGRS-HRTRTCTdggK--NAVFQEKFIFtLIEGLRD-LKVAVWNSNTLSTDDFIGNATIQL 96
Cdd:cd04042  22 DPYVKFKYGGKTvYKSKTIY---KnlNPVWDEKFTL-PIEDVTQpLYIKVFDYDRGLTDDFMGSAFVDL 86

C2 domain second repeat present in Synaptotagmin; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. There are several classes of Synaptotagmins. 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 second C2 repeat, C2B, and has a type-I topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  12 LEVTVVGCQKLKDTEWFSRQDPYVV--LEYGGR---SHRTRTCTdGGKNAVFQEKFIF----TLIEGLrDLKVAVWNSNT 82
Cdd:cd00276  16 LTVVVLKARNLPPSDGKGLSDPYVKvsLLQGGKklkKKKTSVKK-GTLNPVFNEAFSFdvpaEQLEEV-SLVITVVDKDS 93

                        90
                ....*....|..
gi 18418388  83 LSTDDFIGNATI 94
Cdd:cd00276  94 VGRNEVIGQVVL 105

C2 domain second 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 second C2 repeat, C2B, and has a type-II topology.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 18418388  32 DPYVVLEYGGRSHRTRTcTDGGKNAVFQEKFIFTLIEGLRDL-----KVAVWNSNTLSTDDFIGNATIQLQKVLSQE 103
Cdd:cd04011  22 DPVVKVEVGGQKKYTSV-KKGTNCPFYNEYFFFNFHESPDELfdkiiKISVYDSRSLRSDTLIGSFKLDVGTVYDQP 97

C2 domain present in the Human neural precursor cell-expressed, developmentally down-regulated 4 (NEDD4) and NEDD4-like (NEDD4L/NEDD42); Nedd4 and Nedd4-2 are two of the nine members of the Human Nedd4 family. All vertebrates appear to have both Nedd4 and Nedd4-2 genes. They are thought to participate in the regulation of epithelial Na+ channel (ENaC) activity. They also have identical specificity for ubiquitin conjugating enzymes (E2). Nedd4 and Nedd4-2 are composed of a C2 domain, 2-4 WW domains, and a ubiquitin ligase Hect domain. Their WW domains can bind PPxY (PY) or LPSY motifs, and in vitro studies suggest that WW3 and WW4 of both proteins bind PY motifs in the key substrates, with WW3 generally exhibiting higher affinity. Most Nedd4 family members, especially Nedd4-2, also have multiple splice variants, which might play different roles in regulating their substrates. 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 18418388  11 ILEVTVVGCQKLKDTEWFSRQDPYVVLE-YGGRSHRTRTC--TDGGK---NAVFQEKFIFTLIEGLRDLKVAVWNSNTLS 84
Cdd:cd04033   1 ILRVKVLAGIDLAKKDIFGASDPYVKISlYDPDGNGEIDSvqTKTIKktlNPKWNEEFFFRVNPREHRLLFEVFDENRLT 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 18418388  85 TDDFIGNATIQL------QKVLSQEYDDCTWTLQSKT--GRFAGEVQLLLHY 128
Cdd:cd04033  81 RDDFLGQVEVPLnnlpteTPGNERRYTFKDYLLRPRSskSRVKGHLRLYMAY 132

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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  11 ILEVTVVGCQKL--KDTEWFSRQDPYVVLEYGGRSHRTRT---CTDGGKNavFQEKF-IFTLIEGLrdLKVAVWNSNTLS 84
Cdd:cd04024   2 VLRVHVVEAKDLaaKDRSGKGKSDPYAILSVGAQRFKTQTipnTLNPKWN--YWCEFpIFSAQNQL--LKLILWDKDRFA 77

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 18418388  85 TDDFIGNATIQLQKVLSQ---EYDDCTWTLQS----KTGRFAGEVQL 124
Cdd:cd04024  78 GKDYLGEFDIALEEVFADgktGQSDKWITLKStrpgKTSVVSGEIHL 124

C2 domain present in Phosphatidylserine decarboxylase (PSD); PSD is involved in the biosynthesis of aminophospholipid by converting phosphatidylserine (PtdSer) to phosphatidylethanolamine (PtdEtn). There is a single C2 domain present and it is thought to confer PtdSer binding motif that is common to PKC and synaptotagmin. 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 18418388  32 DPYVVLEYGGRSHRTRTCtdggK---NAVFQEKFIFTLI--EGLRDLKVAVWNSNTLSTDDFIGNATIQLQKVLSQEYDD 106
Cdd:cd04039  27 DPFVIISFGRRVFRTSWR----RhtlNPVFNERLAFEVYphEKNFDIQFKVLDKDKFSFNDYVATGSLSVQELLNAAPQP 102

                ....
gi 18418388 107 CTWT 110
Cdd:cd04039 103 DPET 106

C2 domain in Protein Kinase C (PKC) epsilon; A single C2 domain is found in PKC epsilon. The PKC family of serine/threonine kinases regulates apoptosis, proliferation, migration, motility, chemo-resistance, and differentiation. There are 3 groups: group 1 (alpha, betaI, beta II, gamma) which require phospholipids and calcium, group 2 (delta, epsilon, theta, eta) which do not require calcium for activation, and group 3 (xi, iota/lambda) which are atypical and can be activated in the absence of diacylglycerol and calcium. 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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18418388  22 LKDTEWFSRQ----------DPYVVLE----YGGRShRTRTCTDggkNAVFQEKFIFTLIEGlRDLKVAVWNSNTLSTDD 87
Cdd:cd04014  16 LKPTDWSTRHavpkkgsqllDPYVSIDvddtHIGKT-STKPKTN---SPVWNEEFTTEVHNG-RNLELTVFHDAAIGPDD 90

                        90
                ....*....|...
gi 18418388  88 FIGNATIQLQKVL 100
Cdd:cd04014  91 FVANCTISFEDLI 103