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 392920909  84 PEILVGLCYDDKHEVVSVCIEKASSLGSDTAH-PPDSFIRI--IGLDEfstELSRHKTDTVKHSTQPVYShhCTMRF--S 158
Cdd:cd00276    1 GELLLSLSYLPTAERLTVVVLKARNLPPSDGKgLSDPYVKVslLQGGK---KLKKKKTSVKKGTLNPVFN--EAFSFdvP 75

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 392920909 159 KDKVETSTVRVEVwTVTGILRRKVQIGSISIGfASSTPDANEHWQQMMQGAGITVSKWHAI 219
Cdd:cd00276   76 AEQLEEVSLVITV-VDKDSVGRNEVIGQVVLG-PDSGGEELEHWNEMLASPRKPIARWHKL 134

C2 domain second repeat present in Synaptotagmin; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. There are several classes of Synaptotagmins. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920909  84 PEILVGLCYDDKHEVVSVCIEKASSLGSDTAH-PPDSFIRI--IGLDEfstELSRHKTDTVKHSTQPVYShhCTMRF--S 158
Cdd:cd00276    1 GELLLSLSYLPTAERLTVVVLKARNLPPSDGKgLSDPYVKVslLQGGK---KLKKKKTSVKKGTLNPVFN--EAFSFdvP 75

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 392920909 159 KDKVETSTVRVEVwTVTGILRRKVQIGSISIGfASSTPDANEHWQQMMQGAGITVSKWHAI 219
Cdd:cd00276   76 AEQLEEVSLVITV-VDKDSVGRNEVIGQVVLG-PDSGGEELEHWNEMLASPRKPIARWHKL 134

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 392920909    98 VVSVCIEKASSL-GSDTAHPPDSFIRIiGLDEfsTELSRHKTDTVKHSTQPVYSHhcTMRFSKDKVETSTVRVEVWTVTG 176
Cdd:smart00239   1 TLTVKIISARNLpPKDKGGKSDPYVKV-SLDG--DPKEKKKTKVVKNTLNPVWNE--TFEFEVPPPELAELEIEVYDKDR 75

                           90       100
                   ....*....|....*....|....*..
gi 392920909   177 IlRRKVQIGSISIGFaSSTPDANEHWQ 203
Cdd:smart00239  76 F-GRDDFIGQVTIPL-SDLLLGGRHEK 100

C2 domain second repeat present in Synaptotagmin; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. There are several classes of Synaptotagmins. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920909  84 PEILVGLCYDDKHEVVSVCIEKASSLGSDTAH-PPDSFIRI--IGLDEfstELSRHKTDTVKHSTQPVYShhCTMRF--S 158
Cdd:cd00276    1 GELLLSLSYLPTAERLTVVVLKARNLPPSDGKgLSDPYVKVslLQGGK---KLKKKKTSVKKGTLNPVFN--EAFSFdvP 75

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 392920909 159 KDKVETSTVRVEVwTVTGILRRKVQIGSISIGfASSTPDANEHWQQMMQGAGITVSKWHAI 219
Cdd:cd00276   76 AEQLEEVSLVITV-VDKDSVGRNEVIGQVVLG-PDSGGEELEHWNEMLASPRKPIARWHKL 134

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 392920909  85 EILVGLCYDDKHEVVSVCIEKASSLGS-DTAHPPDSFIRIiGLDEFSTELSRHKTDTVKHSTQPVYSHHCTMRFSKDKVE 163
Cdd:cd08405    3 ELLLSLCYNPTANRITVNIIKARNLKAmDINGTSDPYVKV-WLMYKDKRVEKKKTVIKKRTLNPVFNESFIFNIPLERLR 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 392920909 164 TSTVRVEVWTVTGILRRKVqIGSISIGfASSTPDANEHWQQMMQGAGITVSKWHAIQ 220
Cdd:cd08405   82 ETTLIITVMDKDRLSRNDL-IGKIYLG-WKSGGLELKHWKDMLSKPRQPVAQWHRLK 136

C2 domain second repeat present in Synaptotagmin 4; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. 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 392920909  85 EILVGLCYDDKHEVVSVCIEKASSL-GSDTAHPPDSFIRIIGLDEfSTELSRHKTDTVKHSTQPVYSHHCTMRFSKDKVE 163
Cdd:cd08404    3 ELLLSLCYQPTTNRLTVVVLKARHLpKMDVSGLADPYVKVNLYYG-KKRISKKKTHVKKCTLNPVFNESFVFDIPSEELE 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 392920909 164 TSTVRVEVWTVTGILRRKVqIGSISIGfASSTPDANEHWQQMMQGAGITVSKWHAI 219
Cdd:cd08404   82 DISVEFLVLDSDRVTKNEV-IGRLVLG-PKASGSGGHHWKEVCNPPRRQIAEWHML 135

C2 domain first repeat present in Synaptotagmin-like proteins; 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. 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 392920909  85 EILVGLCYDDKHEVVSVCIEKASSL--GSDTAHPPDSFIRIIGLDEFSTElSRHKTDTVKHSTQPVYSHhcTMRF--SKD 160
Cdd:cd08521    2 EIEFSLSYNYKTGSLEVHIKECRNLayADEKKKRSNPYVKVYLLPDKSKQ-SKRKTSVKKNTTNPVFNE--TLKYhiSKS 78

                         90
                 ....*....|..
gi 392920909 161 KVETSTVRVEVW 172
Cdd:cd08521   79 QLETRTLQLSVW 90

C2 domain second repeat found in Tac2-N (Tandem C2 protein in Nucleus); Tac2-N contains two C2 domains and a short C-terminus including a WHXL motif, which are key in stabilizing transport vesicles to the plasma membrane by binding to a plasma membrane. However unlike the usual carboxyl-terminal-type (C-type) tandem C2 proteins, it lacks a transmembrane domain, a Slp-homology domain, and a Munc13-1-interacting domain. Homology search analysis indicate that no known protein motifs are located in its N-terminus, making Tac2-N a novel class of Ca2+-independent, C-type tandem C2 proteins. 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 392920909  85 EILVGLCYDDKHEVVSVCIEKASSLGSDTAHPPDSFIRIIGLdeFSTE--LSRHKTDTVKHSTQPVYSHHcTMRFSKDKV 162
Cdd:cd08692    2 ELQLGTCFQAVNSRIQLQILEAQNLPSSSTPLTLSFFVKVGM--FSTGglLYKKKTRLVKSSNGQVKWGE-TMIFPVTQQ 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 392920909 163 ETSTVRVEVWTVTGILRRKVQIGSISIGFASSTPDANEHWQQMMQGAGITVSKWHAI 219
Cdd:cd08692   79 EHGIQFLIKLYSRSSVRRKHFLGQVWISSDSSSSEAVEQWKDTIANPEKVVTKWHSL 135

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920909   98 VVSVCIEKASSL-GSDTAHPPDSFIRIigldEFSTELSRHKTDTVKHSTQPVYSHhcTMRFSKDKVETSTVRVEVWTVTG 176
Cdd:pfam00168   2 RLTVTVIEAKNLpPKDGNGTSDPYVKV----YLLDGKQKKKTKVVKNTLNPVWNE--TFTFSVPDPENAVLEIEVYDYDR 75

                          90       100
                  ....*....|....*....|....*..
gi 392920909  177 ILRRKVqIGSISIGFAS-STPDANEHW 202
Cdd:pfam00168  76 FGRDDF-IGEVRIPLSElDSGEGLDGW 101

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 392920909  86 ILVGLCYDDKHEVVSVCIEKASSL-GSDTAHPPDSFIRIIgLDEFSTELSRHKTDTVKHSTQPVYSHHCTMRFSKDKVET 164
Cdd:cd08384    2 ILVSLMYNTQRRGLIVGIIRCVNLaAMDANGYSDPFVKLY-LKPDAGKKSKHKTQVKKKTLNPEFNEEFFYDIKHSDLAK 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 392920909 165 STVRVEVWTvTGILRRKVQIGSISIGfASSTPDANEHWQQMMQGAGITVSKWHAI 219
Cdd:cd08384   81 KTLEITVWD-KDIGKSNDYIGGLQLG-INAKGERLRHWLDCLKNPDKKIEAWHTL 133

C2 domain found in Human protein Kibra; Kibra is thought to be a regulator of the Salvador (Sav)/Warts (Wts)/Hippo (Hpo) (SWH) signaling network, which limits tissue growth by inhibiting cell proliferation and promoting apoptosis. The core of the pathway consists of a MST and LATS family kinase cascade that ultimately phosphorylates and inactivates the YAP/Yorkie (Yki) transcription coactivator. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are part of the upstream regulation controlling pathway mechanism. Kibra colocalizes and associates with Mer and Ex and is thought to transduce an extracellular signal via the SWH network. The apical scaffold machinery that contains Hpo, Wts, and Ex recruits Yki to the apical membrane facilitating its inhibitory phosphorlyation by Wts. Since Kibra associates with Ex and is apically located it is hypothesized that KIBRA is part of the scaffold, helps in the Hpo/Wts complex, and helps recruit Yki for inactivation that promotes SWH pathway activity. Kibra contains two amino-terminal WW domains, an internal C2-like domain, and a carboxy-terminal glutamic acid-rich stretch. 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 392920909  84 PEILVGLCYDDKHEVVSVCIEKASSLGSdtAHPPDS---FIRIIGL--DEFSTELSRhkTDTVKHSTQPVYSHHCTMRFS 158
Cdd:cd08680    1 AQVQIGLRYDSGDSSLVISVEQLRNLSA--LSIPENskvYVRVALLpcSSSTSCLFR--TKALEDQDKPVFNEVFRVPIS 76

                         90
                 ....*....|....*...
gi 392920909 159 KDKVETSTVRVEVWTVTG 176
Cdd:cd08680   77 STKLYQKTLQVDVCSVGP 94

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 392920909  85 EILVGLCYDDKHEVVSVCIEKASSLGS-DTAHPPDSFIRIIGLDEfSTELSRHKTDTVKHSTQPVYSHHCTMRFSKDKVE 163
Cdd:cd08403    2 ELMFSLCYLPTAGRLTLTIIKARNLKAmDITGFSDPYVKVSLMCE-GRRLKKKKTSVKKNTLNPTYNEALVFDVPPENVD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 392920909 164 TSTVRVEVWTVTGILRRKVqIGSISIGfASSTPDANEHWQQMMQGAGITVSKWH 217
Cdd:cd08403   81 NVSLIIAVVDYDRVGHNEL-IGVCRVG-PNADGQGREHWNEMLANPRKPIAQWH 132