C2 domain second repeat in Copine; There are 2 copies of the C2 domain present in copine, a protein involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth. 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 1039789726 155 RVITLSLAGRKLDKKDLFGKSDPFLEFYKPGDDGKWMLVHRTEVIKYTLDPVWKPFTVPLVSLCDGDLEKPIQVMCYDYD 234
Cdd:cd04047     1 DVVELQFSGKKLDKKDFFGKSDPFLEISRQSEDGTWVLVYRTEVIKNTLNPVWKPFTIPLQKLCNGDYDRPIKIEVYDYD 80

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1039789726 235 SNGGHDFIGEFQTSVLQMSEARdgvPLEIECIN 267
Cdd:cd04047    81 SSGKHDLIGEFETTLDELLKSS---PLEFELIN 110

Von Willebrand factor type A (vWA) domain was originally found in the blood coagulation protein von Willebrand factor (vWF). Typically, the vWA domain is made up of approximately 200 amino acid residues folded into a classic a/b para-rossmann type of fold. The vWA domain, since its discovery, has drawn great interest because of its widespread occurrence and its involvement in a wide variety of important cellular functions. These include basal membrane formation, cell migration, cell differentiation, adhesion, haemostasis, signaling, chromosomal stability, malignant transformation and in immune defenses In integrins these domains form heterodimers while in vWF it forms multimers. There are different interaction surfaces of this domain as seen by the various molecules it complexes with. Ligand binding in most cases is mediated by the presence of a metal ion dependent adhesion site termed as the MIDAS motif that is a characteristic feature of most, if not all A domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1039789726 279 NSGIIILRSCKIHrnYSFLDYILGGCQLMFTVGIDFTASNGNPLDPSSLHYINPMGTNEYLSAIWAVGQIIQDYD 353
Cdd:cd01459     7 SSGEVTLTDCRVQ--PTFLDYRSAGLESNLIVAIDFTKSNGWPGEKRSLHYISPGRLNPYQKAIRIVGEVLQPYD 79

C2 domain second repeat in Copine; There are 2 copies of the C2 domain present in copine, a protein involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth. 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 1039789726 155 RVITLSLAGRKLDKKDLFGKSDPFLEFYKPGDDGKWMLVHRTEVIKYTLDPVWKPFTVPLVSLCDGDLEKPIQVMCYDYD 234
Cdd:cd04047     1 DVVELQFSGKKLDKKDFFGKSDPFLEISRQSEDGTWVLVYRTEVIKNTLNPVWKPFTIPLQKLCNGDYDRPIKIEVYDYD 80

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1039789726 235 SNGGHDFIGEFQTSVLQMSEARdgvPLEIECIN 267
Cdd:cd04047    81 SSGKHDLIGEFETTLDELLKSS---PLEFELIN 110

VWA Copine: Copines are phospholipid-binding proteins originally identified in paramecium. They are found in human and orthologues have been found in C. elegans and Arabidopsis Thaliana. None have been found in D. Melanogaster or S. Cereviciae. Phylogenetic distribution suggests that copines have been lost in some eukaryotes. No functional properties have been assigned to the VWA domains present in copines. The members of this subgroup contain a functional MIDAS motif based on their preferential binding to magnesium and manganese. However, the MIDAS motif is not totally conserved, in most cases the MIDAS consists of the sequence DxTxS instead of the motif DxSxS that is found in most cases. The C2 domains present in copines mediate phospholipid binding.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1039789726 279 NSGIIILRSCKIHrnYSFLDYILGGCQLMFTVGIDFTASNGNPLDPSSLHYINPMGTNEYLSAIWAVGQIIQDYD 353
Cdd:cd01459     7 SSGEVTLTDCRVQ--PTFLDYRSAGLESNLIVAIDFTKSNGWPGEKRSLHYISPGRLNPYQKAIRIVGEVLQPYD 79

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 1039789726   30 VSGQNLLDRDVTSKSDPFCVLFIedNGRWMEFDRTETAVNNLNPAFSKKFVLDYHFEEVQKLKFALFDQDKSSaqldEHD 109
Cdd:smart00239   7 ISARNLPPKDKGGKSDPYVKVSL--DGDPKEKKKTKVVKNTLNPVWNETFEFEVPPPELAELEIEVYDKDRFG----RDD 80

                           90       100
                   ....*....|....*....|
gi 1039789726  110 FLGQFSCSLGTIVSSKKITR 129
Cdd:smart00239  81 FIGQVTIPLSDLLLGGRHEK 100

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 1039789726  161 LAGRKLDKKDLFGKSDPFLEFYKPGDDGKwmlVHRTEVIKYTLDPVW-KPFTVPLVSLCDgdleKPIQVMCYDYDSNGGH 239
Cdd:smart00239   7 ISARNLPPKDKGGKSDPYVKVSLDGDPKE---KKKTKVVKNTLNPVWnETFEFEVPPPEL----AELEIEVYDKDRFGRD 79

                           90
                   ....*....|...
gi 1039789726  240 DFIGEFQTSVLQM 252
Cdd:smart00239  80 DFIGQVTIPLSDL 92

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1039789726  170 DLFGKSDPFLEFYKPGDDgkwmlVHRTEVIKYTLDPVW-KPFTVPLvslcDGDLEKPIQVMCYDYDSNGGHDFIG 243
Cdd:COG5038   1056 DENGYSDPFVKLFLNEKS-----VYKTKVVKKTLNPVWnEEFTIEV----LNRVKDVLTINVNDWDSGEKNDLLG 1121

C2 domain second repeat in Copine; There are 2 copies of the C2 domain present in copine, a protein involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth. 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 1039789726 155 RVITLSLAGRKLDKKDLFGKSDPFLEFYKPGDDGKWMLVHRTEVIKYTLDPVWKPFTVPLVSLCDGDLEKPIQVMCYDYD 234
Cdd:cd04047     1 DVVELQFSGKKLDKKDFFGKSDPFLEISRQSEDGTWVLVYRTEVIKNTLNPVWKPFTIPLQKLCNGDYDRPIKIEVYDYD 80

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1039789726 235 SNGGHDFIGEFQTSVLQMSEARdgvPLEIECIN 267
Cdd:cd04047    81 SSGKHDLIGEFETTLDELLKSS---PLEFELIN 110

VWA Copine: Copines are phospholipid-binding proteins originally identified in paramecium. They are found in human and orthologues have been found in C. elegans and Arabidopsis Thaliana. None have been found in D. Melanogaster or S. Cereviciae. Phylogenetic distribution suggests that copines have been lost in some eukaryotes. No functional properties have been assigned to the VWA domains present in copines. The members of this subgroup contain a functional MIDAS motif based on their preferential binding to magnesium and manganese. However, the MIDAS motif is not totally conserved, in most cases the MIDAS consists of the sequence DxTxS instead of the motif DxSxS that is found in most cases. The C2 domains present in copines mediate phospholipid binding.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1039789726 279 NSGIIILRSCKIHrnYSFLDYILGGCQLMFTVGIDFTASNGNPLDPSSLHYINPMGTNEYLSAIWAVGQIIQDYD 353
Cdd:cd01459     7 SSGEVTLTDCRVQ--PTFLDYRSAGLESNLIVAIDFTKSNGWPGEKRSLHYISPGRLNPYQKAIRIVGEVLQPYD 79

C2 domain first repeat in Copine; There are 2 copies of the C2 domain present in copine, a protein involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth. 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 1039789726 157 ITLSLAGRKLDKKDLFGKSDPFLEFY-KPGDDGKWMLVHRTEVIKYTLDPVW-KPFTVplvslcDGDLEK--PIQVMCYD 232
Cdd:cd04048     3 VELSISCRNLLDKDVLSKSDPFVVVYvKTGGSGQWVEIGRTEVIKNNLNPDFvTTFTV------DYYFEEvqKLRFEVYD 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1039789726 233 YDSNGG----HDFIGEFQTSVLQMSEARDG-VPLEIECINP 268
Cdd:cd04048    77 VDSKSKdlsdHDFLGEAECTLGEIVSSPGQkLTLPLKGGKG 117

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039789726 161 LAGRKLDKKDLFGKSDPFLEFYKPGDDGKwmlvHRTEVIKYTLDPVW-KPFTVPLVSlcdgDLEKPIQVMCYDYDSNGGH 239
Cdd:pfam00168   8 IEAKNLPPKDGNGTSDPYVKVYLLDGKQK----KKTKVVKNTLNPVWnETFTFSVPD----PENAVLEIEVYDYDRFGRD 79

                          90
                  ....*....|
gi 1039789726 240 DFIGEFQTSV 249
Cdd:pfam00168  80 DFIGEVRIPL 89

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 1039789726  161 LAGRKLDKKDLFGKSDPFLEFYKPGDDGKwmlVHRTEVIKYTLDPVW-KPFTVPLVSLCDgdleKPIQVMCYDYDSNGGH 239
Cdd:smart00239   7 ISARNLPPKDKGGKSDPYVKVSLDGDPKE---KKKTKVVKNTLNPVWnETFEFEVPPPEL----AELEIEVYDKDRFGRD 79

                           90
                   ....*....|...
gi 1039789726  240 DFIGEFQTSVLQM 252
Cdd:smart00239  80 DFIGQVTIPLSDL 92

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 1039789726  22 CVCKVELsVSGQNLLDRD------VTSKSDPFCVLFIEdngrwMEFDRTETAVNNLNPAFSKKFVLDYHFEEVQKLKFAL 95
Cdd:cd08391     1 GVLRIHV-IEAQDLVAKDkfvgglVKGKSDPYVIVRVG-----AQTFKSKVIKENLNPKWNEVYEAVVDEVPGQELEIEL 74

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1039789726  96 FDQDKssaqlDEHDFLGQFSCSLGTIVSSKKITRPLLL 133
Cdd:cd08391    75 FDEDP-----DKDDFLGRLSIDLGSVEKKGFIDEWLPL 107

C2 domain third repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); MCTPs are involved in Ca2+ signaling at the membrane. The cds in this family contain multiple C2 domains as well as a C-terminal PRT domain. 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 third C2 repeat, C2C, and has a type-II topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039789726  33 QNLLDRDVTSKSDPFCVLFIeDNGRWmefdRTETAVNNLNPAFSKKF---VLDYHfeevQKLKFALFDQDKSSAQldehD 109
Cdd:cd08377    11 SGLAAADIGGKSDPFCVLEL-VNARL----QTHTIYKTLNPEWNKIFtfpIKDIH----DVLEVTVYDEDKDKKP----E 77

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1039789726 110 FLGQFSCSLGTIVSSKKITRPLLLMNDKPAGKGVITI 146
Cdd:cd08377    78 FLGKVAIPLLSIKNGERKWYALKDKKLRTRAKGSILL 114

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
                  ....*....|....*....|....*....|....*....|....*....
gi 1039789726 161 LAGRKLDKKDLFGKSDPF--LEFYKPGDDGKWMLVHrTEVIKYTLDPVW 207
Cdd:cd04033     7 LAGIDLAKKDIFGASDPYvkISLYDPDGNGEIDSVQ-TKTIKKTLNPKW 54

Copine; This family represents a conserved region approximately 220 residues long within eukaryotic copines. Copines are Ca(2+)-dependent phospholipid-binding proteins that are thought to be involved in membrane-trafficking, and may also be involved in cell division and growth.

                          10        20
                  ....*....|....*....|....*...
gi 1039789726 326 SLHYINPMGTNEYLSAIWAVGQIIQDYD 353
Cdd:pfam07002   1 SLHYISPSQPNPYEQALRIVGEILQDYD 28

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 1039789726 156 VITLsLAGRKLDKKDLFGKSDPFLEFY---KPGDDGKwmlvHRTEVIKYTLDPVWKP-FTVPLVSLCDGdLEKPIQVMCY 231
Cdd:cd04031    19 IVTV-LQARDLPPRDDGSLRNPYVKVYllpDRSEKSK----RRTKTVKKTLNPEWNQtFEYSNVRRETL-KERTLEVTVW 92

                          90       100       110
                  ....*....|....*....|....*....|
gi 1039789726 232 DYDSNGGHDFIGEFqtsVLQMSEAR-DGVP 260
Cdd:cd04031    93 DYDRDGENDFLGEV---VIDLADALlDDEP 119

C2 domain second repeat present in Synaptotagmin 7; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 7, a member of class 2 synaptotagmins, is located in presynaptic plasma membranes in neurons, dense-core vesicles in endocrine cells, and lysosomes in fibroblasts. It has been shown to play a role in regulation of Ca2+-dependent lysosomal exocytosis in fibroblasts and may also function as a vesicular Ca2+-sensor. It is distinguished from the other synaptotagmins by having over 12 splice forms. 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 1039789726   9 APTAGAIPLGsqccVCKvelsvsGQNLLDRDVTSKSDPFCVLFIEDNGRWMEFDRTETAVNNLNPAFSKKFVLDYHFEEV 88
Cdd:cd08405    11 NPTANRITVN----IIK------ARNLKAMDINGTSDPYVKVWLMYKDKRVEKKKTVIKKRTLNPVFNESFIFNIPLERL 80

                          90       100
                  ....*....|....*....|....*..
gi 1039789726  89 QK--LKFALFDQDKssaqLDEHDFLGQ 113
Cdd:cd08405    81 REttLIITVMDKDR----LSRNDLIGK 103

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039789726  25 KVELsVSGQNLLDRDVTSKSDPFCVLFIEDngrwMEFDRTETAVNNLNPAFSKKFVLDYHFEEVQKLKFALFDQDKSSAQ 104
Cdd:cd04040     2 TVDV-ISAENLPSADRNGKSDPFVKFYLNG----EKVFKTKTIKKTLNPVWNESFEVPVPSRVRAVLKVEVYDWDRGGKD 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1039789726 105 ldehDFLGQFSCSLGTIVSSKKITRPLLLMNDKPAGKGVITI 146
Cdd:cd04040    77 ----DLLGSAYIDLSDLEPEETTELTLPLDGQGGGKLGAVFL 114

C2 domain second repeat present in Synaptotagmin 1; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 1, a member of the class 1 synaptotagmins, is located in the brain and endocranium and localized to the synaptic vesicles and secretory granules. It functions as a Ca2+ sensor for fast exocytosis. It, like synaptotagmin-2, has an N-glycosylated N-terminus. Synaptotagmin 4, a member of class 4 synaptotagmins, is located in the brain. It functions are unknown. It, like synaptotagmin-11, has an Asp to Ser substitution in its C2A domain. 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 1039789726  33 QNLLDRDVTSKSDPFCVLFIEDNGRWMEFDRTETAVNNLNPAFSKKFVLDYHFEEVQK--LKFALFDQDKssaqLDEHDF 110
Cdd:cd08402    25 KNLKKMDVGGLSDPYVKIHLMQNGKRLKKKKTTIKKRTLNPYYNESFSFEVPFEQIQKvhLIVTVLDYDR----IGKNDP 100

                          90
                  ....*....|
gi 1039789726 111 LGQfsCSLGT 120
Cdd:cd08402   101 IGK--VVLGC 108

C2 domain in Protein Kinase C (PKC) alpha and gamma; A single C2 domain is found in PKC alpha and gamma. 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-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039789726 150 ELSDNRVITLSLAGRKLDKKDLFGKSDPFLEFyKPGDDGKWMLVHRTEVIKYTLDPVW-KPFTVPLVslcDGDLEKPIQV 228
Cdd:cd04026     9 SVKDNKLTVEVREAKNLIPMDPNGLSDPYVKL-KLIPDPKNETKQKTKTIKKTLNPVWnETFTFDLK---PADKDRRLSI 84

                          90
                  ....*....|....*..
gi 1039789726 229 MCYDYDSNGGHDFIGEF 245
Cdd:cd04026    85 EVWDWDRTTRNDFMGSL 101

C2A domain first repeat present in Synaptotagmin 8; 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 1039789726  30 VSGQNLLDRDVTSKSDPFC-VLFIEDNGRwmeFDRTETAVNNLNPAFSKKFVLDYHFEEV--QKLKFALFDQDKSSaqld 106
Cdd:cd08387    23 IQARNLQPRDFSGTADPYCkVRLLPDRSN---TKQSKIHKKTLNPEFDESFVFEVPPQELpkRTLEVLLYDFDQFS---- 95

                          90       100
                  ....*....|....*....|....*..
gi 1039789726 107 EHDFLGQFSCSLGTI--VSSKKITRPL 131
Cdd:cd08387    96 RDECIGVVELPLAEVdlSEKLDLWRKI 122

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1039789726  30 VSGQNLLDRDVTSKSDPFCVLfieDNGRWMEFDRTETAVNNLNPAFSKKFVLDYHFEEVQKLKFALFDQDKSSA 103
Cdd:cd04037     7 VRARNLQPKDPNGKSDPYLKI---KLGKKKINDRDNYIPNTLNPVFGKMFELEATLPGNSILKISVMDYDLLGS 77

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1039789726  170 DLFGKSDPFLEFYKPGDDgkwmlVHRTEVIKYTLDPVW-KPFTVPLvslcDGDLEKPIQVMCYDYDSNGGHDFIG 243
Cdd:COG5038   1056 DENGYSDPFVKLFLNEKS-----VYKTKVVKKTLNPVWnEEFTIEV----LNRVKDVLTINVNDWDSGEKNDLLG 1121

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 1039789726 161 LAGRKLDKKDLF--GKSDPFLEFYKpGDDGkwmlvHRTEVIKYTLDPVWKPFT-VPLVSLCDGDLEkpiqVMCYDYDSNG 237
Cdd:cd04024     8 VEAKDLAAKDRSgkGKSDPYAILSV-GAQR-----FKTQTIPNTLNPKWNYWCeFPIFSAQNQLLK----LILWDKDRFA 77

                  ....*...
gi 1039789726 238 GHDFIGEF 245
Cdd:cd04024    78 GKDYLGEF 85

C2 domain second repeat present in Rabphilin and Double C2 domain; Rabphilin is found neurons and in neuroendrocrine cells, while Doc2 is found not only in the brain but in tissues, including mast cells, chromaffin cells, and osteoblasts. 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),7 whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID). 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1039789726 170 DLFGKSDPFLEFYKPGDDGKwMLVHRTEVIKYTLDPVWKP---FTVPLvslcdGDLEKP-IQVMCYDYDSNGGHDFIG 243
Cdd:cd08384    29 DANGYSDPFVKLYLKPDAGK-KSKHKTQVKKKTLNPEFNEeffYDIKH-----SDLAKKtLEITVWDKDIGKSNDYIG 100

C2 domain third repeat present in uncharacterized human KIAA1228-like proteins; KIAA proteins are uncharacterized human proteins. They were compiled by the Kazusa mammalian cDNA project which identified more than 2000 human genes. They are identified by 4 digit codes that precede the KIAA designation. Many KIAA genes are still functionally uncharacterized including KIAA1228. 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 third C2 repeat, C2C, and has a type-II topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039789726  33 QNLLDRDVTSKSDPFCVLFIEDNGRWMEFDRTETAVNNLNPAFSKKFVLDYHFEEVQKLKFALFDQDKSSAQLDEHDFLG 112
Cdd:cd04030    26 RNLPPCDSSDIPDPYVRLYLLPDKSKSTRRKTSVKKDNLNPVFDETFEFPVSLEELKRRTLDVAVKNSKSFLSREKKLLG 105

                          90
                  ....*....|....*.
gi 1039789726 113 QFSCSLGTIVSSKKIT 128
Cdd:cd04030   106 QVLIDLSDLDLSKGFT 121

C2 domain present in Smad ubiquitination-related factor (Smurf)-like proteins; A single C2 domain is found in Smurf proteins, C2-WW-HECT-domain E3s, which play an important role in the downregulation of the TGF-beta signaling pathway. Smurf proteins also regulate cell shape, motility, and polarity by degrading small guanosine triphosphatases (GTPases). 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 type-II topology.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1039789726 155 RVITLSLAGrkLDKKDLFGKSDPFLEFYKPGDDgkwmlVHRTEVIKYTLDPVW 207
Cdd:cd08382     3 RLTVLCADG--LAKRDLFRLPDPFAVITVDGGQ-----THSTDVAKKTLDPKW 48

C2 domain third repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); MCTPs are involved in Ca2+ signaling at the membrane. The cds in this family contain multiple C2 domains as well as a C-terminal PRT domain. 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 third C2 repeat, C2C, and has a type-II topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039789726 164 RKLDKKDLFGKSDPF--LEfykpgddgkwmLVH---RTEVIKYTLDPVW-KPFTVPLvslcdGDLEKPIQVMCYDYDSNG 237
Cdd:cd08377    11 SGLAAADIGGKSDPFcvLE-----------LVNarlQTHTIYKTLNPEWnKIFTFPI-----KDIHDVLEVTVYDEDKDK 74

                          90
                  ....*....|....
gi 1039789726 238 GHDFIGEFQTSVLQ 251
Cdd:cd08377    75 KPEFLGKVAIPLLS 88

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 1039789726 195 RTEVIKYTLDPVW-KPFTVPLVSLCdGDLEK-----PIQVM-CYDYDSNGGHDFIGEFQTS-VLQMSEARDGVP 260
Cdd:cd04017    36 ETEVIKETLSPTWdQTLIFDEVELY-GSPEEiaqnpPLVVVeLFDQDSVGKDEFLGRSVAKpLVKLDLEEDFPP 108

C2 domain second repeat present in Synaptotagmins 3, 5, 6, 9, and 10; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 3, a member of class 3 synaptotagmins, is located in the brain and localized to the active zone and plasma membrane. It functions as a Ca2+ sensor for fast exocytosis. It, along with synaptotagmins 5,6, and 10, has disulfide bonds at its N-terminus. Synaptotagmin 9, a class 5 synaptotagmins, is located in the brain and localized to the synaptic vesicles. It is thought to be a Ca2+-sensor for dense-core vesicle exocytosis. 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 1039789726 164 RKLDKKDLFGKSDPFLEFYKPGdDGKWMLVHRTEVIKYTLDPVWKP---FTVPLVSLCDGDLEkpIQVMcyDYDSNGGHD 240
Cdd:cd08403    24 RNLKAMDITGFSDPYVKVSLMC-EGRRLKKKKTSVKKNTLNPTYNEalvFDVPPENVDNVSLI--IAVV--DYDRVGHNE 98

                  ...
gi 1039789726 241 FIG 243
Cdd:cd08403    99 LIG 101