C2 domain second 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 1179685215 712 LGPAQLVGRQTLATPAMGDIQIGMEDKKGQLEVEVIRARSLTQKPGSKSTPAPYVKVYLLENGACIAKKKTRIARKTLDP 791
Cdd:cd04028     1 LGPGQLVGRQVLASPSMGDIQLGLYDKKGQLEVEVIRARGLVQKPGSKVLPAPYVKVYLLEGKKCIAKKKTKIARKTLDP 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1179685215 792 LYQQSLVFDESPQGKVLQVIVWGDYGRMDHKCFMGVAQILLEELDLSSMVIGWYKLFPPSSLVDPT 857
Cdd:cd04028    81 LYQQQLVFDVSPTGKTLQVIVWGDYGRMDKKVFMGVAQILLDDLDLSNLVIGWYKLFPTSSLVDPT 146

PDZ domain of Rab3-interacting molecule 1 (RIM), RIM2, piccolo and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of RIM, RIM2, piccolo and related domains. RIM proteins and Gallus gallus protein piccolo (also called aczonin) are involved in neurotransmitter release at presynaptic active zones, the site of vesicle fusion. A protein complex containing RIM proteins positions synaptic vesicles containing synaptotagmin at the active zone. RIM proteins simultaneously activate docking and priming of synaptic vesicles and recruit Ca2+-channels to active zones, thereby connecting primed synaptic vesicles to Ca2+-channels. RIM binding to vesicular Rab proteins (Rab3 and Rab27 isoforms) mediates vesicle docking; RIM binding to Munc13 activates vesicle priming; RIM binding to the Ca2+-channel, both directly and indirectly via RIM-BP, recruits the Ca2+-channels. The RIM PDZ domain interacts with the C-termini of N- and P/Q-type voltage-gated Ca2+-channels. RIM1, RIM2 and piccolo also participate in regulated exocytosis through binding cAMP-GEFII (cAMP-binding protein-guanidine nucleotide exchange factor II). The piccolo PDZ domain binds cAMP-GEFII. RIM2 also plays a role in dendrite formation by melanocytes. Caenorhabditis elegans RIM (also known as unc-10) may be involved in the regulation of defecation and daumone response. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This RIM-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215   1 MPKDSGALLGLKVVGGKMTDLGRLGAFITKVKKGSLADVVGHLRAGDEVLEWNGKPLPGATNEEVYNIILESKsePQVEI 80
Cdd:cd06714    15 DGSVSGNGLGLKVVGGKMTESGRLGAYVTKVKPGSVADTVGHLREGDEVLEWNGISLQGKTFEEVQDIISQSK--GEVEL 92

                  ...
gi 1179685215  81 IVS 83
Cdd:cd06714    93 VVS 95

C2 domain second 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 1179685215 712 LGPAQLVGRQTLATPAMGDIQIGMEDKKGQLEVEVIRARSLTQKPGSKSTPAPYVKVYLLENGACIAKKKTRIARKTLDP 791
Cdd:cd04028     1 LGPGQLVGRQVLASPSMGDIQLGLYDKKGQLEVEVIRARGLVQKPGSKVLPAPYVKVYLLEGKKCIAKKKTKIARKTLDP 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1179685215 792 LYQQSLVFDESPQGKVLQVIVWGDYGRMDHKCFMGVAQILLEELDLSSMVIGWYKLFPPSSLVDPT 857
Cdd:cd04028    81 LYQQQLVFDVSPTGKTLQVIVWGDYGRMDKKVFMGVAQILLDDLDLSNLVIGWYKLFPTSSLVDPT 146

PDZ domain of Rab3-interacting molecule 1 (RIM), RIM2, piccolo and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of RIM, RIM2, piccolo and related domains. RIM proteins and Gallus gallus protein piccolo (also called aczonin) are involved in neurotransmitter release at presynaptic active zones, the site of vesicle fusion. A protein complex containing RIM proteins positions synaptic vesicles containing synaptotagmin at the active zone. RIM proteins simultaneously activate docking and priming of synaptic vesicles and recruit Ca2+-channels to active zones, thereby connecting primed synaptic vesicles to Ca2+-channels. RIM binding to vesicular Rab proteins (Rab3 and Rab27 isoforms) mediates vesicle docking; RIM binding to Munc13 activates vesicle priming; RIM binding to the Ca2+-channel, both directly and indirectly via RIM-BP, recruits the Ca2+-channels. The RIM PDZ domain interacts with the C-termini of N- and P/Q-type voltage-gated Ca2+-channels. RIM1, RIM2 and piccolo also participate in regulated exocytosis through binding cAMP-GEFII (cAMP-binding protein-guanidine nucleotide exchange factor II). The piccolo PDZ domain binds cAMP-GEFII. RIM2 also plays a role in dendrite formation by melanocytes. Caenorhabditis elegans RIM (also known as unc-10) may be involved in the regulation of defecation and daumone response. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This RIM-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215   1 MPKDSGALLGLKVVGGKMTDLGRLGAFITKVKKGSLADVVGHLRAGDEVLEWNGKPLPGATNEEVYNIILESKsePQVEI 80
Cdd:cd06714    15 DGSVSGNGLGLKVVGGKMTESGRLGAYVTKVKPGSVADTVGHLREGDEVLEWNGISLQGKTFEEVQDIISQSK--GEVEL 92

                  ...
gi 1179685215  81 IVS 83
Cdd:cd06714    93 VVS 95

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215 740 GQLEVEVIRARSLTQKPGSkSTPAPYVKVYLLEngaCIAKKKTRIARKTLDPLYQQSLVFD-ESPQGKVLQVIVWgDYGR 818
Cdd:pfam00168   1 GRLTVTVIEAKNLPPKDGN-GTSDPYVKVYLLD---GKQKKKTKVVKNTLNPVWNETFTFSvPDPENAVLEIEVY-DYDR 75

                          90       100
                  ....*....|....*....|....*....
gi 1179685215 819 MDHKCFMGVAQILLEELDLSSMVIGWYKL 847
Cdd:pfam00168  76 FGRDDFIGEVRIPLSELDSGEGLDGWYPL 104

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 1179685215  741 QLEVEVIRARSLtQKPGSKSTPAPYVKVYLleNGACIAKKKTRIARKTLDPLYQQSLVFD-ESPQGKVLQVIVWgDYGRM 819
Cdd:smart00239   1 TLTVKIISARNL-PPKDKGGKSDPYVKVSL--DGDPKEKKKTKVVKNTLNPVWNETFEFEvPPPELAELEIEVY-DKDRF 76

                           90       100
                   ....*....|....*....|....*
gi 1179685215  820 DHKCFMGVAQILLEELDLSSMVIGW 844
Cdd:smart00239  77 GRDDFIGQVTIPLSDLLLGGRHEKL 101

PDZ domain; PDZ domains are found in diverse signaling proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215   1 MPKDSGALLGLKVVGGkmTDLGRLGAFITKVKKGSLADVVGhLRAGDEVLEWNGKPLPGATNEEVYNIILESKSEPQVEI 80
Cdd:pfam00595   4 LEKDGRGGLGFSLKGG--SDQGDPGIFVSEVLPGGAAEAGG-LKVGDRILSINGQDVENMTHEEAVLALKGSGGKVTLTI 80

                  .
gi 1179685215  81 I 81
Cdd:pfam00595  81 L 81

Periplasmic serine protease, S1-C subfamily, contain C-terminal PDZ domain [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215  25 GAFITKVKKGSLADVVGhLRAGDEVLEWNGKPLPGAtnEEVYNIILESKSEPQVEIIVSR 84
Cdd:COG0265   202 GVLVARVEPGSPAAKAG-LRPGDVILAVDGKPVTSA--RDLQRLLASLKPGDTVTLTVLR 258

C2 domain second 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 1179685215 712 LGPAQLVGRQTLATPAMGDIQIGMEDKKGQLEVEVIRARSLTQKPGSKSTPAPYVKVYLLENGACIAKKKTRIARKTLDP 791
Cdd:cd04028     1 LGPGQLVGRQVLASPSMGDIQLGLYDKKGQLEVEVIRARGLVQKPGSKVLPAPYVKVYLLEGKKCIAKKKTKIARKTLDP 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1179685215 792 LYQQSLVFDESPQGKVLQVIVWGDYGRMDHKCFMGVAQILLEELDLSSMVIGWYKLFPPSSLVDPT 857
Cdd:cd04028    81 LYQQQLVFDVSPTGKTLQVIVWGDYGRMDKKVFMGVAQILLDDLDLSNLVIGWYKLFPTSSLVDPT 146

PDZ domain of Rab3-interacting molecule 1 (RIM), RIM2, piccolo and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of RIM, RIM2, piccolo and related domains. RIM proteins and Gallus gallus protein piccolo (also called aczonin) are involved in neurotransmitter release at presynaptic active zones, the site of vesicle fusion. A protein complex containing RIM proteins positions synaptic vesicles containing synaptotagmin at the active zone. RIM proteins simultaneously activate docking and priming of synaptic vesicles and recruit Ca2+-channels to active zones, thereby connecting primed synaptic vesicles to Ca2+-channels. RIM binding to vesicular Rab proteins (Rab3 and Rab27 isoforms) mediates vesicle docking; RIM binding to Munc13 activates vesicle priming; RIM binding to the Ca2+-channel, both directly and indirectly via RIM-BP, recruits the Ca2+-channels. The RIM PDZ domain interacts with the C-termini of N- and P/Q-type voltage-gated Ca2+-channels. RIM1, RIM2 and piccolo also participate in regulated exocytosis through binding cAMP-GEFII (cAMP-binding protein-guanidine nucleotide exchange factor II). The piccolo PDZ domain binds cAMP-GEFII. RIM2 also plays a role in dendrite formation by melanocytes. Caenorhabditis elegans RIM (also known as unc-10) may be involved in the regulation of defecation and daumone response. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This RIM-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215   1 MPKDSGALLGLKVVGGKMTDLGRLGAFITKVKKGSLADVVGHLRAGDEVLEWNGKPLPGATNEEVYNIILESKsePQVEI 80
Cdd:cd06714    15 DGSVSGNGLGLKVVGGKMTESGRLGAYVTKVKPGSVADTVGHLREGDEVLEWNGISLQGKTFEEVQDIISQSK--GEVEL 92

                  ...
gi 1179685215  81 IVS 83
Cdd:cd06714    93 VVS 95

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215 740 GQLEVEVIRARSLTQKPGSkSTPAPYVKVYLLEngaCIAKKKTRIARKTLDPLYQQSLVFD-ESPQGKVLQVIVWgDYGR 818
Cdd:pfam00168   1 GRLTVTVIEAKNLPPKDGN-GTSDPYVKVYLLD---GKQKKKTKVVKNTLNPVWNETFTFSvPDPENAVLEIEVY-DYDR 75

                          90       100
                  ....*....|....*....|....*....
gi 1179685215 819 MDHKCFMGVAQILLEELDLSSMVIGWYKL 847
Cdd:pfam00168  76 FGRDDFIGEVRIPLSELDSGEGLDGWYPL 104

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 1179685215 127 ALKDAPQVLPGQLSVKLwydKVGHQLIVNVLQATDLPARVDGRPRNPYVKMYFLPDRSDKSKRRTKTVKKILEPKWNQTF 206
Cdd:cd04020     7 ALKYVPPESEGALKSKK---PSTGELHVWVKEAKNLPALKSGGTSDSFVKCYLLPDKSKKSKQKTPVVKKSVNPVWNHTF 83

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1179685215 207 VYSHVHRRDFRERMLEITVWDQPRVQeeESEFLG 240
Cdd:cd04020    84 VYDGVSPEDLSQACLELTVWDHDKLS--SNDFLG 115

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 1179685215 729 GDIQIGMEDKKGQLEVEVIRARSLtqKPGSKSTPAPYVKVYLLENGACIAKKKTRIARKTLDPLYQQSLVFDESP----Q 804
Cdd:cd08381     2 GQVKLSISYKNGTLFVMVMHAKNL--PLLDGSDPDPYVKTYLLPDPQKTTKRKTKVVRKTRNPTFNEMLVYDGLPvedlQ 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1179685215 805 GKVLQVIVWGDyGRMDHKCFMGVAQILLEELDLSSMVIGWYKL 847
Cdd:cd08381    80 QRVLQVSVWSH-DSLVENEFLGGVCIPLKKLDLSQETEKWYPL 121

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 1179685215  151 QLIVNVLQATDLPARVDGRPRNPYVKMYFLPDRsdKSKRRTKTVKKILEPKWNQTFVYSHVHRRDfreRMLEITVWDQPR 230
Cdd:smart00239   1 TLTVKIISARNLPPKDKGGKSDPYVKVSLDGDP--KEKKKTKVVKNTLNPVWNETFEFEVPPPEL---AELEIEVYDKDR 75

                           90       100
                   ....*....|....*....|....*...
gi 1179685215  231 VQEEesEFLGEILIELETALLDDEPHWY 258
Cdd:smart00239  76 FGRD--DFIGQVTIPLSDLLLGGRHEKL 101

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 1179685215 152 LIVNVLQATDLPARVDGRPRNPYVKMYFLpdrsDKSKRRTKTVKKILEPKWNQTFVYSHVhrrDFRERMLEITVWDQPRV 231
Cdd:cd00030     1 LRVTVIEARNLPAKDLNGKSDPYVKVSLG----GKQKFKTKVVKNTLNPVWNETFEFPVL---DPESDTLTVEVWDKDRF 73

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1179685215 232 QEEesEFLGEILIELETALLDDEPH--WYKL 260
Cdd:cd00030    74 SKD--DFLGEVEIPLSELLDSGKEGelWLPL 102

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 1179685215 729 GDIQIGM--EDKKGQLEVEVIRARSLTQKPGSKSTPAPYVKVYLLENGACIAKKKTRIARKTLDPLYQQSLVFDESPQ-- 804
Cdd:cd08521     1 GEIEFSLsyNYKTGSLEVHIKECRNLAYADEKKKRSNPYVKVYLLPDKSKQSKRKTSVKKNTTNPVFNETLKYHISKSql 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1179685215 805 -GKVLQVIVWgDYGRMDHKCFMGVAQILLEELDLSSMVIGWYKL 847
Cdd:cd08521    81 eTRTLQLSVW-HHDRFGRNTFLGEVEIPLDSWDLDSQQSEWYPL 123

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215   1 MPKDSGALLGLKVVGGKMTDLGrlgAFITKVKKGSLADVVGHLRAGDEVLEWNGKPLPGATNEEVYNIILESKSEpqVEI 80
Cdd:cd00136     4 LEKDPGGGLGFSIRGGKDGGGG---IFVSRVEPGGPAARDGRLRVGDRILEVNGVSLEGLTHEEAVELLKSAGGE--VTL 78

                  ..
gi 1179685215  81 IV 82
Cdd:cd00136    79 TV 80

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 1179685215 742 LEVEVIRARSLtQKPGSKSTPAPYVKVYLLENgaciAKKKTRIARKTLDPLYQQSLVFD-ESPQGKVLQVIVWgDYGRMD 820
Cdd:cd00030     1 LRVTVIEARNL-PAKDLNGKSDPYVKVSLGGK----QKFKTKVVKNTLNPVWNETFEFPvLDPESDTLTVEVW-DKDRFS 74

                          90       100
                  ....*....|....*....|....*...
gi 1179685215 821 HKCFMGVAQILLEELDLSSMVI-GWYKL 847
Cdd:cd00030    75 KDDFLGEVEIPLSELLDSGKEGeLWLPL 102

C2A domain first repeat present in Synaptotagmins 1, 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 1, a member of 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 as do synaptotagmins 5, 6, and 10. It is distinguished from the other synaptotagmins by having an N-glycosylated N-terminus. Synaptotagmins 5, 6, and 10, members of class 3 synaptotagmins, are located primarily in the brain and localized to the active zone and plasma membrane. They is distinguished from the other synaptotagmins by having disulfide bonds at its N-terminus. Synaptotagmin 6 also regulates the acrosome reaction, a unique Ca2+-regulated exocytosis, in sperm. 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 first C2 repeat, C2A, and has a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215 137 GQLSVKLWYDKVGHQLIVNVLQATDLPARVDGRPRNPYVKMYFLPDRsdKSKRRTKTVKKILEPKWNQTFVYShVHRRDF 216
Cdd:cd08385     3 GKLQFSLDYDFQSNQLTVGIIQAADLPAMDMGGTSDPYVKVYLLPDK--KKKFETKVHRKTLNPVFNETFTFK-VPYSEL 79

                          90
                  ....*....|.
gi 1179685215 217 RERMLEITVWD 227
Cdd:cd08385    80 GNKTLVFSVYD 90

C2A domain first repeat present in Synaptotagmins 15 and 17; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. It is thought to be involved in the trafficking and exocytosis of secretory vesicles in non-neuronal tissues and is Ca2+ independent. Human synaptotagmin 15 has 2 alternatively spliced forms that encode proteins with different C-termini. The larger, SYT15a, contains a N-terminal TM region, a putative fatty-acylation site, and 2 tandem C terminal C2 domains. The smaller, SYT15b, lacks the C-terminal portion of the second C2 domain. Unlike most other synaptotagmins it is nearly absent in the brain and rather is found in the heart, lungs, skeletal muscle, and testis. 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 first C2 repeat, C2A, and has a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215 137 GQLSVKLWYDKVGHQLIVNVLQATDLPAR-VDGRPRNPYVKMYFLPDrsDKSKRRTKTVKKILEPKWNQTFVYShVHRRD 215
Cdd:cd08390     1 GRLWFSVQYDLEEEQLTVSLIKARNLPPRtKDVAHCDPFVKVCLLPD--ERRSLQSKVKRKTQNPNFDETFVFQ-VSFKE 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1179685215 216 FRERMLEITVWD--QPRVQEEesefLGEILIELETALLDDEPHWYK 259
Cdd:cd08390    78 LQRRTLRLSVYDvdRFSRHCI----IGHVLFPLKDLDLVKGGVVWR 119

C2 domain first repeat present in Synaptotagmin-like proteins 1 and 2; 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 Slp3 and Slp4/granuphilin which 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. 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 1179685215 729 GDIQIGM--EDKKGQLEVEVIRARSLTQKPGSKSTPAPYVKVYLLENGACIAKKKTRIARKTLDPLYQQSL---VFDESP 803
Cdd:cd08393     2 GSVQFALdyDPKLRELHVHVIQCQDLAAADPKKQRSDPYVKTYLLPDKSNRGKRKTSVKKKTLNPVFNETLrykVEREEL 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1179685215 804 QGKVLQVIVWgDYGRMDHKCFMGVAQILLEELDLSSMVIGWYKL 847
Cdd:cd08393    82 PTRVLNLSVW-HRDSLGRNSFLGEVEVDLGSWDWSNTQPTWYPL 124

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 1179685215 729 GDIQIGMEDKKGQLEVEVIRARSLT-QKPGSKSTPapYVKVYLLENGACIAKKKTRIARKTLDPLYQQSLVFDESPQGK- 806
Cdd:cd04026     2 GRIYLKISVKDNKLTVEVREAKNLIpMDPNGLSDP--YVKLKLIPDPKNETKQKTKTIKKTLNPVWNETFTFDLKPADKd 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1179685215 807 -VLQVIVWgDYGRMDHKCFMGVAQILLEELdLSSMVIGWYKL 847
Cdd:cd04026    80 rRLSIEVW-DWDRTTRNDFMGSLSFGVSEL-IKMPVDGWYKL 119

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 1179685215 729 GDIQIGME--DKKGQLEVEVIRARSLTQKPGSKStPAPYVKVYLLENGACIAKKKTRIARKTLDPLYQQSLVFDESP--- 803
Cdd:cd04030     3 GRIQLTIRysSQRQKLIVTVHKCRNLPPCDSSDI-PDPYVRLYLLPDKSKSTRRKTSVKKDNLNPVFDETFEFPVSLeel 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1179685215 804 QGKVLQVIVWGDYGRMD-HKCFMGVAQILLEELDLSSMVIGWYKL 847
Cdd:cd04030    82 KRRTLDVAVKNSKSFLSrEKKLLGQVLIDLSDLDLSKGFTQWYDL 126

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215    5 SGALLGLKVVGGKMTDLGrlgAFITKVKKGSLADVVGhLRAGDEVLEWNGKPLPGATNEEVYNIILESKSEpqVEIIVSR 84
Cdd:smart00228  10 GGGGLGFSLVGGKDEGGG---VVVSSVVPGSPAAKAG-LRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGK--VTLTVLR 83

                   .
gi 1179685215   85 P 85
Cdd:smart00228  84 G 84

C2 domain first repeat present in Synaptotagmin-like protein 3; 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. Little is known about the expression or localization of Slp3. The C2A domain of Slp3 is Ca2+ dependent. It has been demonstrated that Slp3 promotes 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 first C2 repeat, C2A, and has a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215 137 GQLSVKLWYDKVGHQLIVNVLQATDLPARVDGRPR-NPYVKMYFLPDRSDKSKRRTKTVKKILEPKWNQTFVYShVHRRD 215
Cdd:cd08392     2 GEIEFALHYNFRTSCLEITIKACRNLAYGDEKKKKcHPYVKVCLLPDKSHNSKRKTAVKKGTVNPVFNETLKYV-VEADL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1179685215 216 FRERMLEITVWDQPRVQEEesEFLGEILIELETALLDDEP----HWYKL 260
Cdd:cd08392    81 LSSRQLQVSVWHSRTLKRR--VFLGEVLIPLADWDFEDTDsqrfLWYPL 127

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 1179685215 729 GDI--QIGMEDKKGQLEVEVIRARSLTQKPGSKSTPAPYVKVYLLENGACIAKKKTRIARKTLDPLYQQSLVFDESP--- 803
Cdd:cd04029     2 GEIlfSLSYDYKTQSLNVHVKECRNLAYGDEAKKRSNPYVKTYLLPDKSRQSKRKTSIKRNTTNPVYNETLKYSISHsql 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1179685215 804 QGKVLQVIVWgDYGRMDHKCFMGVAQILLEELDLSSMVIGWYKL 847
Cdd:cd04029    82 ETRTLQLSVW-HYDRFGRNTFLGEVEIPLDSWNFDSQHEECLPL 124

C2A domain first repeat present in Synaptotagmins 15 and 17; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. It is thought to be involved in the trafficking and exocytosis of secretory vesicles in non-neuronal tissues and is Ca2+ independent. Human synaptotagmin 15 has 2 alternatively spliced forms that encode proteins with different C-termini. The larger, SYT15a, contains a N-terminal TM region, a putative fatty-acylation site, and 2 tandem C terminal C2 domains. The smaller, SYT15b, lacks the C-terminal portion of the second C2 domain. Unlike most other synaptotagmins it is nearly absent in the brain and rather is found in the heart, lungs, skeletal muscle, and testis. 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 first C2 repeat, C2A, and has a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1179685215 741 QLEVEVIRARSLTQKPGSKSTPAPYVKVYLLENGACiaKKKTRIARKTLDPLYQQSLVFDESP---QGKVLQVIVWgDYG 817
Cdd:cd08390    15 QLTVSLIKARNLPPRTKDVAHCDPFVKVCLLPDERR--SLQSKVKRKTQNPNFDETFVFQVSFkelQRRTLRLSVY-DVD 91