C2 domain found in the Human KIAA0528 cDNA clone; The members of this CD are named after the Human KIAA0528 cDNA clone. All members here contain a single C2 repeat. No other information on this protein is currently known. 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 221459022    5 VGVKIKAARNLPVMDKSSETTDAFVEIKLASVTHKTDVFRKSLNPTWNTDWFRFEVDDAELQDEPLQIRLMDYDTYSAND 84
Cdd:cd08688     1 LKVRVVAARDLPVMDRSSDLTDAFVEVKFGSTTYKTDVVKKSLNPVWNSEWFRFEVDDEELQDEPLQIRVMDHDTYSAND 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 221459022   85 AIGKVNISLNPLCLESSSqavhgkgTVLSGWIPVFDT 121
Cdd:cd08688    81 AIGKVYIDLNPLLLKDSV-------SQISGWFPIYDT 110

C2 domain found in the Human KIAA0528 cDNA clone; The members of this CD are named after the Human KIAA0528 cDNA clone. All members here contain a single C2 repeat. No other information on this protein is currently known. 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 221459022    5 VGVKIKAARNLPVMDKSSETTDAFVEIKLASVTHKTDVFRKSLNPTWNTDWFRFEVDDAELQDEPLQIRLMDYDTYSAND 84
Cdd:cd08688     1 LKVRVVAARDLPVMDRSSDLTDAFVEVKFGSTTYKTDVVKKSLNPVWNSEWFRFEVDDEELQDEPLQIRVMDHDTYSAND 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 221459022   85 AIGKVNISLNPLCLESSSqavhgkgTVLSGWIPVFDT 121
Cdd:cd08688    81 AIGKVYIDLNPLLLKDSV-------SQISGWFPIYDT 110

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 221459022      7 VKIKAARNLPVMDKSSeTTDAFVEIKLA---SVTHKTDVFRKSLNPTWNTDwFRFEVDDAELQDepLQIRLMDYDTYSAN 83
Cdd:smart00239    4 VKIISARNLPPKDKGG-KSDPYVKVSLDgdpKEKKKTKVVKNTLNPVWNET-FEFEVPPPELAE--LEIEVYDKDRFGRD 79

                            90       100
                    ....*....|....*....|
gi 221459022     84 DAIGKVNISLNPLCLESSSQ 103
Cdd:smart00239   80 DFIGQVTIPLSDLLLGGRHE 99

C2 domain found in the Human KIAA0528 cDNA clone; The members of this CD are named after the Human KIAA0528 cDNA clone. All members here contain a single C2 repeat. No other information on this protein is currently known. 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 221459022    5 VGVKIKAARNLPVMDKSSETTDAFVEIKLASVTHKTDVFRKSLNPTWNTDWFRFEVDDAELQDEPLQIRLMDYDTYSAND 84
Cdd:cd08688     1 LKVRVVAARDLPVMDRSSDLTDAFVEVKFGSTTYKTDVVKKSLNPVWNSEWFRFEVDDEELQDEPLQIRVMDHDTYSAND 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 221459022   85 AIGKVNISLNPLCLESSSqavhgkgTVLSGWIPVFDT 121
Cdd:cd08688    81 AIGKVYIDLNPLLLKDSV-------SQISGWFPIYDT 110

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 221459022    7 VKIKAARNLPVMDKSSeTTDAFVEIKLASV-THKTDVFRKSLNPTWNtDWFRFEVDDaeLQDEPLQIRLMDYDTYSANDA 85
Cdd:cd00030     3 VTVIEARNLPAKDLNG-KSDPYVKVSLGGKqKFKTKVVKNTLNPVWN-ETFEFPVLD--PESDTLTVEVWDKDRFSKDDF 78

                          90
                  ....*....|....*...
gi 221459022   86 IGKVNISLNPLCLESSSQ 103
Cdd:cd00030    79 LGEVEIPLSELLDSGKEG 96

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    7 VKIKAARNLPVMDKSSeTTDAFVEIKL-ASVTHK--TDVFRKSLNPTWNtDWFRFEVDDAE-LQDEPLQIRLMDYDTYSA 82
Cdd:cd08386    20 LKILKAVELPAKDFSG-TSDPFVKIYLlPDKKHKleTKVKRKNLNPHWN-ETFLFEGFPYEkLQQRVLYLQVLDYDRFSR 97

                          90
                  ....*....|....*....
gi 221459022   83 NDAIGKVNISLNPLCLESS 101
Cdd:cd08386    98 NDPIGEVSLPLNKVDLTEE 116

C2 domain first repeat; fungal group; C2 domains were first identified in Protein Kinase C (PKC). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    3 GKVGVKIKAARNLPVMDKSSETTDAFVEIKLASV---THKTDVFRKSLNPTWNTDWFRFEVDDAELQDEPLQIRLMDYDT 79
Cdd:cd04041     1 GVLVVTIHRATDLPKADFGTGSSDPYVTASFAKFgkpLYSTRIIRKDLNPVWEETWFVLVTPDEVKAGERLSCRLWDSDR 80

                          90
                  ....*....|....*..
gi 221459022   80 YSANDAIGKVNISLNPL 96
Cdd:cd04041    81 FTADDRLGRVEIDLKEL 97

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 221459022    1 MPGKVGVKIKAARNLPVMDKSSeTTDAFVEIKLasvTH--------KTDVFRKSLNPTWNTDwFRFEVDDAELQDEPLQI 72
Cdd:cd08405    13 TANRITVNIIKARNLKAMDING-TSDPYVKVWL---MYkdkrvekkKTVIKKRTLNPVFNES-FIFNIPLERLRETTLII 87

                          90       100
                  ....*....|....*....|
gi 221459022   73 RLMDYDTYSANDAIGKVNIS 92
Cdd:cd08405    88 TVMDKDRLSRNDLIGKIYLG 107

C2 domain second repeat present in Synaptotagmin-like proteins 1-4; All Slp members basically share an N-terminal Slp homology domain (SHD) and C-terminal tandem C2 domains (named the C2A domain and the C2B domain) with the SHD and C2 domains being separated by a linker sequence of various length. Slp1/JFC1 and Slp2/exophilin 4 promote granule docking to the plasma membrane. Additionally, their C2A domains are both Ca2+ independent, unlike the case in Slp3 and Slp4/granuphilin in which their C2A domains are Ca2+ dependent. It is thought that SHD (except for the Slp4-SHD) functions as a specific Rab27A/B-binding domain. In addition to Slps, rabphilin, Noc2, and Munc13-4 also function as Rab27-binding proteins. It has been demonstrated that Slp3 and Slp4/granuphilin promote dense-core vesicle exocytosis. 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 221459022    3 GKVGVKIKAARNLPVMdKSSETTDAFVEIKL-----ASVTHKTDVFRKSLNPTWNTDwFRFE-VDDAELQDEPLQIRLMD 76
Cdd:cd04020    27 GELHVWVKEAKNLPAL-KSGGTSDSFVKCYLlpdksKKSKQKTPVVKKSVNPVWNHT-FVYDgVSPEDLSQACLELTVWD 104

                          90
                  ....*....|....*..
gi 221459022   77 YDTYSANDAIGKVNISL 93
Cdd:cd04020   105 HDKLSSNDFLGGVRLGL 121

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 221459022    3 GKVGVKIKAARNLPVMDKSSeTTDAFVEIKL-----ASVTHKTDVFRKSLNPTWNTDwFRFEVDDAELqDEPLQIRLMDY 77
Cdd:cd04026    13 NKLTVEVREAKNLIPMDPNG-LSDPYVKLKLipdpkNETKQKTKTIKKTLNPVWNET-FTFDLKPADK-DRRLSIEVWDW 89

                          90
                  ....*....|....*....
gi 221459022   78 DTYSANDAIGKVNISLNPL 96
Cdd:cd04026    90 DRTTRNDFMGSLSFGVSEL 108

C2A domain first repeat present in Synaptotagmins 4 and 11; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmins 4 and 11, class 4 synaptotagmins, are located in the brain. Their functions are unknown. They are distinguished from the other synaptotagmins by having and Asp to Ser substitution in their C2A 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 221459022    6 GVKIKAARNLPVMDKSSETTDAFVEIK-LASVTH--KTDVFRKSLNPTWNTDWFRFEVDDAELQDEPLQIRLMDYDTYSA 82
Cdd:cd08388    19 LVNIIECRDLPAMDEQSGTSDPYVKLQlLPEKEHkvKTRVLRKTRNPVYDETFTFYGIPYNQLQDLSLHFAVLSFDRYSR 98

                          90
                  ....*....|....*....
gi 221459022   83 NDAIGKVNISLNPLCLESS 101
Cdd:cd08388    99 DDVIGEVVCPLAGADLLNE 117

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 221459022    7 VKIKAARNLPVMDKSSeTTDAFVEIKL---ASVTHK--TDVFRKSLNPTWNTDWFRFEVDDAELQDEPLQIRLMDYDTYS 81
Cdd:cd04031    20 VTVLQARDLPPRDDGS-LRNPYVKVYLlpdRSEKSKrrTKTVKKTLNPEWNQTFEYSNVRRETLKERTLEVTVWDYDRDG 98

                          90
                  ....*....|..
gi 221459022   82 ANDAIGKVNISL 93
Cdd:cd04031    99 ENDFLGEVVIDL 110

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    7 VKIKAARNLPVMDkSSETTDAFVEIKLASVT-----HKTDVFRKSLNPTWNtDWFRFEVDDAELQDEPLQIRLMDYDTYS 81
Cdd:cd08384    17 VGIIRCVNLAAMD-ANGYSDPFVKLYLKPDAgkkskHKTQVKKKTLNPEFN-EEFFYDIKHSDLAKKTLEITVWDKDIGK 94

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 221459022   82 ANDAIGKVNISLnplclesssqavHGKGTVLSGWIPVF 119
Cdd:cd08384    95 SNDYIGGLQLGI------------NAKGERLRHWLDCL 120

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 221459022    7 VKIKAARNLPVMDkSSETTDAFVEIKL---ASVTHKTDVFRKSLNPTWNTDwFRFEVDDAELQDEPLQIRLMDYDTYSAN 83
Cdd:cd08387    20 VKLIQARNLQPRD-FSGTADPYCKVRLlpdRSNTKQSKIHKKTLNPEFDES-FVFEVPPQELPKRTLEVLLYDFDQFSRD 97

                          90
                  ....*....|
gi 221459022   84 DAIGKVNISL 93
Cdd:cd08387    98 ECIGVVELPL 107

C2 domain present in Intersectin; A single instance of the C2 domain is located C terminally in the intersectin protein. Intersectin functions as a scaffolding protein, providing a link between the actin cytoskeleton and the components of endocytosis and plays a role in signal transduction. In addition to C2, intersectin contains several additional domains including: Eps15 homology domains, SH3 domains, a RhoGEF domain, and a PH 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. The members here have topology I.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    3 GKVGVKIKAARNLPVMDKSSETtDAFVEIKLASVTHKTDVFRKSLNPTWNTDwFRFEVDDaeLQDEPLQIRLMDYDTYSA 82
Cdd:cd08375    15 GRLMVVIVEGRDLKPCNSNGKS-DPYCEVSMGSQEHKTKVVSDTLNPKWNSS-MQFFVKD--LEQDVLCITVFDRDFFSP 90

                          90
                  ....*....|.
gi 221459022   83 NDAIGKVNISL 93
Cdd:cd08375    91 DDFLGRTEIRV 101

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 221459022   11 AARNLPVMD---KSsettDAFVEIKLAS------VTHKTDVFRKSLNPTWNTdwfrFEVDDAEL----QDEPLQIRLMDY 77
Cdd:cd04047     8 SGKKLDKKDffgKS----DPFLEISRQSedgtwvLVYRTEVIKNTLNPVWKP----FTIPLQKLcngdYDRPIKIEVYDY 79

                          90
                  ....*....|....*....
gi 221459022   78 DTYSANDAIGKVNISLNPL 96
Cdd:cd04047    80 DSSGKHDLIGEFETTLDEL 98

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    3 GKVGVKIKAARNLPVMDKSSETtDAFVEIKLAS-VTHKTDVFRKSLNPTWNTDwFRFEVDdAELQDEpLQIRLMDYDTYS 81
Cdd:COG5038  1040 GYLTIMLRSGENLPSSDENGYS-DPFVKLFLNEkSVYKTKVVKKTLNPVWNEE-FTIEVL-NRVKDV-LTINVNDWDSGE 1115

                          90       100
                  ....*....|....*....|..
gi 221459022   82 ANDAIGKVNISLNPLCLESSSQ 103
Cdd:COG5038  1116 KNDLLGTAEIDLSKLEPGGTTN 1137

C2 domain present in the putative elicitor-responsive gene; In plants elicitor-responsive proteins are triggered in response to specific elicitor molecules such as glycolproteins, peptides, carbohydrates and lipids. A host of defensive responses are also triggered resulting in localized cell death. Antimicrobial secondary metabolites, such as phytoalexins, or defense-related proteins, including pathogenesis-related (PR) proteins are also produced. There is a single C2 domain present here. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members have a type-II topology.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 221459022   26 DAFVEIKLASVTHKTDVFR-KSLNPTWNtDWFRFEVDDAELQ-DEPLQIRLMDYDTYSANDAIGKVNISLNPLCLESS 101
Cdd:cd04049    23 DPYVIIQCRTQERKSKVAKgDGRNPEWN-EKFKFTVEYPGWGgDTKLILRIMDKDNFSDDDFIGEATIHLKGLFEEGV 99

C2 domain second repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); MCTPs are involved in Ca2+ signaling at the membrane. MCTP is composed of a variable N-terminal sequence, three C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022   12 ARNLPVMDKSSeTTDAFVEIKLASVTHKTDVFRKSLNPTWnTDWFRFEVDDAelQDEPLQIRLMDYDTYSANDAIGKVNI 91
Cdd:cd08376     9 GKNLPPMDDNG-LSDPYVKFRLGNEKYKSKVCSKTLNPQW-LEQFDLHLFDD--QSQILEIEVWDKDTGKKDEFIGRCEI 84

                  ....*...
gi 221459022   92 SLNPLCLE 99
Cdd:cd08376    85 DLSALPRE 92

C2 domain second repeat present in class II phosphatidylinositol 3-kinases (PI3Ks); There are 3 classes of PI3Ks based on structure, regulation, and specificity. All classes contain a N-terminal C2 domain, a PIK domain, and a kinase catalytic domain. Unlike class I and class III, class II PI3Ks have additionally a PX domain and a C-terminal C2 domain containing a nuclear localization signal both of which bind phospholipids though in a slightly different fashion. PI3Ks (AKA phosphatidylinositol (PtdIns) 3-kinases) regulate cell processes such as cell growth, differentiation, proliferation, and motility. PI3Ks work on phosphorylation of phosphatidylinositol, phosphatidylinositide (4)P (PtdIns (4)P),2 or PtdIns(4,5)P2. Specifically they phosphorylate the D3 hydroxyl group of phosphoinositol lipids on the inositol ring. 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 221459022    3 GKVGVKIKAARNLPVMDKSSetTDAFVEIKLASVTH-----KTDVFRKSLNPTWNTDWFRFEVDDAELQDEPLQIRLMDY 77
Cdd:cd08381    13 GTLFVMVMHAKNLPLLDGSD--PDPYVKTYLLPDPQkttkrKTKVVRKTRNPTFNEMLVYDGLPVEDLQQRVLQVSVWSH 90

                          90       100
                  ....*....|....*....|.
gi 221459022   78 DTYSANDAIGKVNISLNPLCL 98
Cdd:cd08381    91 DSLVENEFLGGVCIPLKKLDL 111

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    3 GKVGVKIKAARNLPVMDKS-SETTDAFVEIKLASVTH-KTDVFRKSLNPTWNTDWFrfevddAELQ--DEPLQIRLMDYD 78
Cdd:COG5038   436 GVVEVKIKSAEGLKKSDSTiNGTVDPYITVTFSDRVIgKTRVKKNTLNPVWNETFY------ILLNsfTDPLNLSLYDFN 509

                          90
                  ....*....|....*...
gi 221459022   79 TYSANDAIGKVNISLNPL 96
Cdd:COG5038   510 SFKSDKVVGSTQLDLALL 527

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    7 VKIKAARNLPvMDKSSETTDAFVEIKLASVTHKTDVFRKSLNPTWNTDwFRFEVDDAELQDepLQIRLMDYDTysaNDAI 86
Cdd:cd04050     4 VYLDSAKNLP-LAKSTKEPSPYVELTVGKTTQKSKVKERTNNPVWEEG-FTFLVRNPENQE--LEIEVKDDKT---GKSL 76

                  ....*..
gi 221459022   87 GKVNISL 93
Cdd:cd04050    77 GSLTLPL 83

C2 domain third repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); plant subset; MCTPs are involved in Ca2+ signaling at the membrane. Plant-MCTPs are composed of a variable N-terminal sequence, four C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    7 VKIKAARNLPVMDKSsETTDAFVEIKLASVTHKTDV-FRKSLNPTWNTDwFRFEVddAELQDEPLQIRLMDYDTYSANDA 85
Cdd:cd04019     4 VTVIEAQDLVPSDKN-RVPEVFVKAQLGNQVLRTRPsQTRNGNPSWNEE-LMFVA--AEPFEDHLILSVEDRVGPNKDEP 79

                  ....*....
gi 221459022   86 IGKVNISLN 94
Cdd:cd04019    80 LGRAVIPLN 88

C2 domain first repeat in Munc13 (mammalian uncoordinated)-like 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 221459022   34 ASVTHKTDVFRKSLNPTWNtDWFRFEVDDaeLQDEPLQIRLMDYDtysaNDAIGKVNISLN 94
Cdd:cd08676    87 AKSIKVTEVKPQTLNPVWN-ETFRFEVED--VSNDQLHLDIWDHD----DDFLGCVNIPLK 140

C2 domain second repeat present in Synaptotagmin 17; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 17 is located in the brain, kidney, and prostate and is thought to be a peripheral membrane protein. 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 221459022    3 GKVGVKIKAARNLPVMDkSSETTDAFVEIKLAS-----VTHKTDVFRKSLNPTWNtDWFRFEVDDAELQDEPLQIRLMDY 77
Cdd:cd08410    14 GRLNVDIIRAKQLLQTD-MSQGSDPFVKIQLVHglkliKTKKTSCMRGTIDPFYN-ESFSFKVPQEELENVSLVFTVYGH 91

                          90
                  ....*....|....
gi 221459022   78 DTYSANDAIGKVNI 91
Cdd:cd08410    92 NVKSSNDFIGRIVI 105

C2 domain first repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); plant subset; MCTPs are involved in Ca2+ signaling at the membrane. Plant-MCTPs are composed of a variable N-terminal sequence, four C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-II topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    4 KVGVKIKAARNLPVMDKSSeTTDAFVEIKLASVTHKTDVFRKSLNPTWNtDWFRFEVDDAE-LQDEPLQIRLMDyDTYS- 81
Cdd:cd04022     1 KLVVEVVDAQDLMPKDGQG-SSSAYVELDFDGQKKRTRTKPKDLNPVWN-EKLVFNVSDPSrLSNLVLEVYVYN-DRRSg 77

                          90
                  ....*....|..
gi 221459022   82 -ANDAIGKVNIS 92
Cdd:cd04022    78 rRRSFLGRVRIS 89

C2 domain first repeat present in Synaptotagmin-like proteins 4 and 5; All Slp members basically share an N-terminal Slp homology domain (SHD) and C-terminal tandem C2 domains (named the C2A domain and the C2B domain) with the SHD and C2 domains being separated by a linker sequence of various length. SHD of Slp (except for the Slp4-SHD) function as a specific Rab27A/B-binding domain. In addition to Slp, rabphilin, Noc2, and Munc13-4 also function as Rab27-binding proteins. It has been demonstrated that Slp4/granuphilin promotes dense-core vesicle exocytosis. The C2A domain of Slp4 is Ca2+ dependent. Slp5 mRNA has been shown to be restricted to human placenta and liver suggesting a role in Rab27A-dependent membrane trafficking in specific tissues. 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 221459022    7 VKIKAARNLPVMDKSSETTDAFVEI-----KLASVTHKTDVFRKSLNPTWNtDWFRFEVDDAELQDEPLQIRLMDYDTYS 81
Cdd:cd04029    19 VHVKECRNLAYGDEAKKRSNPYVKTyllpdKSRQSKRKTSIKRNTTNPVYN-ETLKYSISHSQLETRTLQLSVWHYDRFG 97

                          90
                  ....*....|....*....
gi 221459022   82 ANDAIGKVNISLNPLCLES 100
Cdd:cd04029    98 RNTFLGEVEIPLDSWNFDS 116

C2 domain third 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 third C2 repeat, C2C, and has a type-II topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 221459022    7 VKIKAARNLPVMDKS-------------SETTDAFVEIKLASVTHKTDVFRKSLNPTWNtdwfrfevDDAELQD------ 67
Cdd:cd04018     4 FKIYRAEDLPQMDSGimanvkkaflgekKELVDPYVEVSFAGQKVKTSVKKNSYNPEWN--------EQIVFPEmfpplc 75

                          90       100
                  ....*....|....*....|....*.
gi 221459022   68 EPLQIRLMDYDTYSANDAIGKVNISL 93
Cdd:cd04018    76 ERIKIQIRDWDRVGNDDVIGTHFIDL 101

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 221459022    7 VKIKAARNLPVMDKSSeTTDAFVEIKLASVTHKTDVFRKSLNPTWNtDWFRFEVDDAElqdEPLQIRLMDYDTYSANDAI 86
Cdd:cd08377     5 VKVIRASGLAAADIGG-KSDPFCVLELVNARLQTHTIYKTLNPEWN-KIFTFPIKDIH---DVLEVTVYDEDKDKKPEFL 79