C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863   605 GLIELVLVEARDLVAADIRGTSDPYVRVQY--GEKKQRTKVIYKTLQPKWNQTMEF---PDDGSSLELHVKDYNTLLPTS 679
Cdd:pfam00168   1 GRLTVTVIEAKNLPPKDGNGTSDPYVKVYLldGKQKKKTKVVKNTLNPVWNETFTFsvpDPENAVLEIEVYDYDRFGRDD 80

                          90       100
                  ....*....|....*....|....
gi 18401863   680 SIGNCVVEYQGLKPNETADKWIIL 703
Cdd:pfam00168  81 FIGEVRIPLSELDSGEGLDGWYPL 104

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863   605 GLIELVLVEARDLVAADIRGTSDPYVRVQY--GEKKQRTKVIYKTLQPKWNQTMEF---PDDGSSLELHVKDYNTLLPTS 679
Cdd:pfam00168   1 GRLTVTVIEAKNLPPKDGNGTSDPYVKVYLldGKQKKKTKVVKNTLNPVWNETFTFsvpDPENAVLEIEVYDYDRFGRDD 80

                          90       100
                  ....*....|....*....|....
gi 18401863   680 SIGNCVVEYQGLKPNETADKWIIL 703
Cdd:pfam00168  81 FIGEVRIPLSELDSGEGLDGWYPL 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 18401863    606 LIELVLVEARDLVAADIRGTSDPYVRVQYG---EKKQRTKVIYKTLQPKWNQTMEF---PDDGSSLELHVKDYNTLLPTS 679
Cdd:smart00239   1 TLTVKIISARNLPPKDKGGKSDPYVKVSLDgdpKEKKKTKVVKNTLNPVWNETFEFevpPPELAELEIEVYDKDRFGRDD 80

                           90       100
                   ....*....|....*....|.
gi 18401863    680 SIGNCVVEYQGLKPNETADKW 700
Cdd:smart00239  81 FIGQVTIPLSDLLLGGRHEKL 101

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863  549 EEMLGTDNIGTATLSLQGINNSemhIWVPLEDVNSGEIELLIEALDPEYSEADSSK--GLIELVLVEARDLVAADIRGTS 626
Cdd:COG5038  985 DKVVCEVTLPTLDLVSNAYEKP---SSLNFPGSAKVLVQVSYTPVPVKLPPVEMVEnsGYLTIMLRSGENLPSSDENGYS 1061

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863  627 DPYVRVQYGEKK-QRTKVIYKTLQPKWNQ--TMEFP-DDGSSLELHVKDYNTLLPTSSIGNCVVEYQGLKPNETAD---- 698
Cdd:COG5038 1062 DPFVKLFLNEKSvYKTKVVKKTLNPVWNEefTIEVLnRVKDVLTINVNDWDSGEKNDLLGTAEIDLSKLEPGGTTNsnip 1141

                        170       180       190
                 ....*....|....*....|....*....|....*..
gi 18401863  699 ---KWII-LQGVKHGEVHVRVTRKVTEIQRRASAGPG 731
Cdd:COG5038 1142 ldgKTFIvLDGTLHPGFNFRSKYALNVSRKEGILGDI 1178

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 18401863    482 KIIVTVLAGKNLVSKDKSGKCDASVKLQYG---KIIQKTKIVNAAEC-VWNQKFEFE-ELAGEEYLKVKCYREEMLGTD- 555
Cdd:smart00239   1 TLTVKIISARNLPPKDKGGKSDPYVKVSLDgdpKEKKKTKVVKNTLNpVWNETFEFEvPPPELAELEIEVYDKDRFGRDd 80

                           90       100
                   ....*....|....*....|
gi 18401863    556 NIGTATLSLQGINNSEMHIW 575
Cdd:smart00239  81 FIGQVTIPLSDLLLGGRHEK 100

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863   605 GLIELVLVEARDLVAADIRGTSDPYVRVQY--GEKKQRTKVIYKTLQPKWNQTMEF---PDDGSSLELHVKDYNTLLPTS 679
Cdd:pfam00168   1 GRLTVTVIEAKNLPPKDGNGTSDPYVKVYLldGKQKKKTKVVKNTLNPVWNETFTFsvpDPENAVLEIEVYDYDRFGRDD 80

                          90       100
                  ....*....|....*....|....
gi 18401863   680 SIGNCVVEYQGLKPNETADKWIIL 703
Cdd:pfam00168  81 FIGEVRIPLSELDSGEGLDGWYPL 104

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 605 GLIELVLVEARDLVAADI------RGTSDPYVRVQYGEKKQRTKVIYKTLQPKWNQTMEF---PDDGSSLELHV------ 669
Cdd:cd08391   1 GVLRIHVIEAQDLVAKDKfvgglvKGKSDPYVIVRVGAQTFKSKVIKENLNPKWNEVYEAvvdEVPGQELEIELfdedpd 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 18401863 670 KDYNtllptssIGNCVVEYQGLKPNETADKWIILQGVKHGEVHVRVT 716
Cdd:cd08391  81 KDDF-------LGRLSIDLGSVEKKGFIDEWLPLEDVKSGRLHLKLE 120

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 605 GLIELVLVEARDLVAADIR--GTSDPYVRVQYGEKKQRTKVIYKTLQPKWNQTMEFP---DDGSSLELHVKDYNTLLPTS 679
Cdd:cd04024   1 GVLRVHVVEAKDLAAKDRSgkGKSDPYAILSVGAQRFKTQTIPNTLNPKWNYWCEFPifsAQNQLLKLILWDKDRFAGKD 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 18401863 680 SIGNCVVEYQGLKPN---ETADKWIILQ-------GVKHGEVHVRVT 716
Cdd:cd04024  81 YLGEFDIALEEVFADgktGQSDKWITLKstrpgktSVVSGEIHLQFS 127

C2 domain second repeat present in RasA1 and RasA4; RasA1 and RasA4 are GAP1s (GTPase activating protein 1s ), Ras-specific GAP members, which suppresses Ras function by enhancing the GTPase activity of Ras proteins resulting in the inactive GDP-bound form of Ras. In this way it can control cellular proliferation and differentiation. Both proteins contain two C2 domains, a Ras-GAP domain, a plextrin homology (PH)-like domain, and a Bruton's Tyrosine Kinase (BTK) zinc binding 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. This cd contains the second C2 repeat, C2B, and has a type-I topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 611 LVEARDLVAADIRGTSDPYVRVQYGEKKQRTKVIYKTLQPKWNQTMEFPDDG---SSLELHVKDYNTLLPTSSIGNCVVE 687
Cdd:cd04025   6 VLEARDLAPKDRNGTSDPFVRVFYNGQTLETSVVKKSCYPRWNEVFEFELMEgadSPLSVEVWDWDLVSKNDFLGKVVFS 85

                        90
                ....*....|....*..
gi 18401863 688 YQGLKPNETADKWIILQ 704
Cdd:cd04025  86 IQTLQQAKQEEGWFRLL 102

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 18401863 605 GLIELVLVEARDLVAADIRGTSDPYVRVQYGEKKQRTKVIYKTLQPKWNQTMEFP--DDGSSLELHVKDYN--------- 673
Cdd:cd08377   1 GFLQVKVIRASGLAAADIGGKSDPFCVLELVNARLQTHTIYKTLNPEWNKIFTFPikDIHDVLEVTVYDEDkdkkpeflg 80

                        90       100
                ....*....|....*....|
gi 18401863 674 -TLLPTSSIGNCVVEYQGLK 692
Cdd:cd08377  81 kVAIPLLSIKNGERKWYALK 100

C2 domain fourth repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the fifth C2 repeat, C2E, and has a type-II topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 611 LVEARDLVAADIRGTSDPYVRVQY-GEKKQRTKVIYKTLQPKWNQTMEFP---DDGSSLELHVKDYNTLLPTSSIGNCVV 686
Cdd:cd04040   5 VISAENLPSADRNGKSDPFVKFYLnGEKVFKTKTIKKTLNPVWNESFEVPvpsRVRAVLKVEVYDWDRGGKDDLLGSAYI 84

                        90       100       110
                ....*....|....*....|....*....|.
gi 18401863 687 EYQGLKPNETADKWIIL---QGVKHGEVHVR 714
Cdd:cd04040  85 DLSDLEPEETTELTLPLdgqGGGKLGAVFLP 115

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 18401863 603 SKGLIELVLVEARDLVAADIRGTSDPYVRV--QYGEK---KQRTKVIYKTLQPKWNQTMEF--PDD---GSSLELHVKDY 672
Cdd:cd08405  13 TANRITVNIIKARNLKAMDINGTSDPYVKVwlMYKDKrveKKKTVIKKRTLNPVFNESFIFniPLErlrETTLIITVMDK 92

                        90
                ....*....|
gi 18401863 673 NTLLPTSSIG 682
Cdd:cd08405  93 DRLSRNDLIG 102

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 18401863 623 RGTSDPYVRVQYGEKKQRTKVIYKTLQPKWNQTMEFP-----DDGSSLELHVKDYNTLLPTSSIGNCVV 686
Cdd:cd08373  12 KGKGDRIAKVTFRGVKKKTRVLENELNPVWNETFEWPlagspDPDESLEIVVKDYEKVGRNRLIGSATV 80

synaptotagmin-like mitochondrial-lipid-binding protein (SMP) domain found in the synaptotagmin family, mostly plants; The synaptotagmin family includes Arabidopsis thaliana synaptotagmins (AtSYT1-5) and similar proteins. AtSYT1, also called NTMC2T1.1, or synaptotagmin A (SYTA), plays an important role in maintaining plasma membrane integrity during freezing and osmotic stresses. It may function in membrane resealing during calcium-dependent freezing tolerance. It regulates endocytosis and endosome recycling at the plasma membrane and cell-to-cell trafficking of cabbage leaf curl virus (CaLCuV) and tobacco mosaic virus (TMV) movement proteins via plasmodesmata. AtSYT2, also called NTMC2T1.2, or synaptotagmin B (SYTB), may play an important role in regulating an unconventional protein trafficking from the cytosol to the extracellular matrix. AtSYT3 (also called NTMC2T1.3, or synaptotagmin C, or SYTC), AtSYT4 (also called NTMC2T2.2, or synaptotagmin D, or SYTD) and AtSYT5 (also called NTMC2T2.1, or synaptotagmin E, or SYTE) may also be involved in membrane trafficking. This model corresponds to the SMP domain of SYT family proteins, which may be implicated in lipid transport.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863  96 EHCQWLNKLLSEIWlNYMNKKLSLRFSSMVEKRLRQRRSRLIENIQLLEFSLGSCPPLLG---LHGTcwskSGEQKIMRL 172
Cdd:cd21677  10 ERVDWLNKLLEKLW-PYLDKAASKLVKESVEPLLEQYKPSFISSIKFKKLTLGTVPPRIEgvkVVES----DEDEVILDV 84

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 173 DFNWDTtDLSILLQAKLsmPFNRTARIVVNSLCIKGD--ILIRPILE-----GrALLYSFVSNPEVRIGVAFGggggqSL 245
Cdd:cd21677  85 DFRWAG-DPDIVLAVKL--LPGLSLPVQVKDLQLSGTvrITLKPLVDelpcfG-AVSVSLVEKPVVDFDLKLL-----GG 155

                       170       180
                ....*....|....*....|....*....
gi 18401863 246 PATELPGVSSWLVKILTETLNKKMVEPRR 274
Cdd:cd21677 156 DDMALPGLKSWLDSFIRDALLDMLVWPKR 184

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 18401863 612 VEARDLVAADIRGTSDPYVRVQYGEKKQRTKVIYKTLQPKWNQTMEF----PDDGSSLELHVKDYN 673
Cdd:cd04022   7 VDAQDLMPKDGQGSSSAYVELDFDGQKKRTRTKPKDLNPVWNEKLVFnvsdPSRLSNLVLEVYVYN 72

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 485 VTVLAGKNLVSKDKS------GKCDASVKLQYGKIIQKTKIV-NAAECVWNQKFEF--EELAGEEyLKVKCYREEMLGTD 555
Cdd:cd08391   5 IHVIEAQDLVAKDKFvgglvkGKSDPYVIVRVGAQTFKSKVIkENLNPKWNEVYEAvvDEVPGQE-LEIELFDEDPDKDD 83

                        90       100       110
                ....*....|....*....|....*....|....
gi 18401863 556 NIGTATLSLQGI-NNSEMHIWVPLEDVNSGEIEL 588
Cdd:cd08391  84 FLGRLSIDLGSVeKKGFIDEWLPLEDVKSGRLHL 117

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 18401863    482 KIIVTVLAGKNLVSKDKSGKCDASVKLQYG---KIIQKTKIVNAAEC-VWNQKFEFE-ELAGEEYLKVKCYREEMLGTD- 555
Cdd:smart00239   1 TLTVKIISARNLPPKDKGGKSDPYVKVSLDgdpKEKKKTKVVKNTLNpVWNETFEFEvPPPELAELEIEVYDKDRFGRDd 80

                           90       100
                   ....*....|....*....|
gi 18401863    556 NIGTATLSLQGINNSEMHIW 575
Cdd:smart00239  81 FIGQVTIPLSDLLLGGRHEK 100

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 18401863 595 PEYSEADSSKGLIELV-LVEARDLVAADIRGTSDPYVRV---QYGEKKQRTKVIYKTLQPKWNQTMEF---PDD---GSS 664
Cdd:cd08386   5 IQFSVSYDFQESTLTLkILKAVELPAKDFSGTSDPFVKIyllPDKKHKLETKVKRKNLNPHWNETFLFegfPYEklqQRV 84

                        90
                ....*....|....*...
gi 18401863 665 LELHVKDYNTLLPTSSIG 682
Cdd:cd08386  85 LYLQVLDYDRFSRNDPIG 102

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 18401863 584 GEIELLIEALDpeyseadsskGLIELVLVEARDLVAADIRGTSDPYVRVQY-----GEKKQRTKVIYKTLQPKWNQTMEF 658
Cdd:cd04026   2 GRIYLKISVKD----------NKLTVEVREAKNLIPMDPNGLSDPYVKLKLipdpkNETKQKTKTIKKTLNPVWNETFTF 71

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 597 YSEADSSkglIELVLVEARDLVAADIRGTSDPYVRVQY--GEKK---QRTKVIYKTLQPKWNQTMEF----PDDGSSLEL 667
Cdd:cd04035  10 YDPANSA---LHCTIIRAKGLKAMDANGLSDPYVKLNLlpGASKatkLRTKTVHKTRNPEFNETLTYygitEEDIQRKTL 86

                        90       100       110
                ....*....|....*....|....*....|....
gi 18401863 668 HVkdynTLLPTSSIGNCVV-EY----QGLKPNET 696
Cdd:cd04035  87 RL----LVLDEDRFGNDFLgETriplKKLKPNQT 116

C2 domain found in fungal Ingression 1 (Inn1) proteins; Saccharomyces cerevisiae Inn1 associates with the contractile actomyosin ring at the end of mitosis and is needed for cytokinesis. The C2 domain of Inn1, located at the N-terminus, is required for ingression of the plasma membrane. The C-terminus is relatively unstructured and contains eight PXXP motifs that are thought to mediate interaction of Inn1 with other proteins with SH3 domains in the cytokinesis proteins Hof1 (an F-BAR protein) and Cyk3 (whose overexpression can restore primary septum formation in Inn1Delta cells) as well as recruiting Inn1 to the bud-neck by binding to Cyk3. Inn1 and Cyk3 appear to cooperate in activating chitin synthase Chs2 for primary septum formation, which allows coordination of actomyosin ring contraction with ingression of the cleavage furrow. It is thought that the C2 domain of Inn1 helps to preserve the link between the actomyosin ring and the plasma membrane, contributing both to membrane ingression, as well as to stability of the contracting ring. Additionally, Inn1 might induce curvature of the plasma membrane adjacent to the contracting ring, thereby promoting ingression of the membrane. It has been shown that the C2 domain of human synaptotagmin induces curvature in target membranes and thereby contributes to fusion of these membranes with synaptic vesicles. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 605 GLIELVLVEARDLVAADIRGTSDPYVRVQYGEKKQRTKVIYKTLQ-PKWNQTMEF---PDDGSSLELHVKDYNTLLPTsS 680
Cdd:cd08681   1 GTLVVVVLKARNLPNKRKLDKQDPYCVLRIGGVTKKTKTDFRGGQhPEWDEELRFeitEDKKPILKVAVFDDDKRKPD-L 79

                        90       100       110
                ....*....|....*....|....*....|....*...
gi 18401863 681 IGNCVVEYQGLKPNETADKWIILQ--GVKHGEVHVRVT 716
Cdd:cd08681  80 IGDTEVDLSPALKEGEFDDWYELTlkGRYAGEVYLELT 117

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 18401863 605 GLIELVLVEARDLVAADIRGTSDPYVRVQY---GE--KKQRTKVIYKTLQPKWNQTMEF---PD--DGSSLELHVKDYNT 674
Cdd:cd08403  14 GRLTLTIIKARNLKAMDITGFSDPYVKVSLmceGRrlKKKKTSVKKNTLNPTYNEALVFdvpPEnvDNVSLIIAVVDYDR 93

                        90
                ....*....|..
gi 18401863 675 LLPTSSIGNCVV 686
Cdd:cd08403  94 VGHNELIGVCRV 105

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 18401863 584 GEIELLIEaldpeYSEADSSkgLIELVLvEARDLVAADIRGTSDPYVRV-----QYGEKKQRTKVIYKTLQPKWNQTMEF 658
Cdd:cd04030   3 GRIQLTIR-----YSSQRQK--LIVTVH-KCRNLPPCDSSDIPDPYVRLyllpdKSKSTRRKTSVKKDNLNPVFDETFEF 74

                        90       100
                ....*....|....*....|....*..
gi 18401863 659 P---DDGSS--LELHVKDYNTLLPTSS 680
Cdd:cd04030  75 PvslEELKRrtLDVAVKNSKSFLSREK 101

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 614 ARDLVAADIRGTSDPYVRVQY-------GEKKQRTKVIYKTLQPKWNQTMEF--PDDGSSLE---LH--VKDYNTLLPTS 679
Cdd:cd04009  25 ARNLLPLDSNGSSDPFVKVELlprhlfpDVPTPKTQVKKKTLFPLFDESFEFnvPPEQCSVEgalLLftVKDYDLLGSND 104

                ....*..
gi 18401863 680 SIGNCVV 686
Cdd:cd04009 105 FEGEAFL 111

C2 domain second repeat present in Synaptotagmin 1; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 1, a member of the class 1 synaptotagmins, is located in the brain and endocranium and localized to the synaptic vesicles and secretory granules. It functions as a Ca2+ sensor for fast exocytosis. It, like synaptotagmin-2, has an N-glycosylated N-terminus. Synaptotagmin 4, a member of class 4 synaptotagmins, is located in the brain. It functions are unknown. It, like synaptotagmin-11, has an Asp to Ser substitution in its C2A domain. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 603 SKGLIELVLVEARDLVAADIRGTSDPYVRVQYGE-----KKQRTKVIYKTLQPKWNQTMEF---PDDGSSLELHVK--DY 672
Cdd:cd08402  13 TAGKLTVVILEAKNLKKMDVGGLSDPYVKIHLMQngkrlKKKKTTIKKRTLNPYYNESFSFevpFEQIQKVHLIVTvlDY 92

                        90
                ....*....|....
gi 18401863 673 NTLLPTSSIGNCVV 686
Cdd:cd08402  93 DRIGKNDPIGKVVL 106

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 485 VTVLAGKNLVSKD--KSGKCDASVKLQYGKIIQKTKIVNaaECV---WNQKFEFE-ELAGEEYLKVKCY-REEMLGTDNI 557
Cdd:cd04024   5 VHVVEAKDLAAKDrsGKGKSDPYAILSVGAQRFKTQTIP--NTLnpkWNYWCEFPiFSAQNQLLKLILWdKDRFAGKDYL 82

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 18401863 558 GTATLSLQGINN---SEMHI-WVPLED-------VNSGEIEL 588
Cdd:cd04024  83 GEFDIALEEVFAdgkTGQSDkWITLKStrpgktsVVSGEIHL 124

synaptotagmin-like mitochondrial-lipid-binding protein (SMP) domain of the extended synaptotagmin (E-Syt) family; The extended synaptotagmin (E-Syt) family includes a group of Ca2+-regulated intrinsic membrane proteins, such as E-Syt1, E-Syt2 and E-Syt3. They are composed of an N-terminal endoplasmic reticulum (ER)-membrane anchor, a central SMP-domain, and five (E-Syt1) or three C-terminal cytoplasmic C2-domains (E-Syt2 and E-Syt3). The ER-membrane anchor and C2 domains are required for tethering, while the SMP domain is a lipid-binding domain that links the ER with other lipid bilayer-membranes within the cell. This model corresponds to the SMP domain, which has a beta-barrel structure like protein modules in the tubular-lipid-binding (TULIP) superfamily. It dimerizes to form an approximately 90-Angstrom-long cylinder traversed by a channel lined entirely with hydrophobic residues. The following two C2 domains then form arched structures flexibly linked to the SMP domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863  96 EHCQWLNKLLSEIWLN---YMNKKLSlrfsSMVEKRLRQRRSRLIENIQLLEFSLGSCPPLLGlHGTCWSKSGEQK--IM 170
Cdd:cd21670   1 ERAEWLNKIIKQLWPYineYVEKLLK----EKIEPSIRALLPGPLKSFRFEKIDLGDKPPRIG-GVKVYTDNVDRDeiIL 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18401863 171 RLDFNWDTTdlsillqAKLSMPFNRTARIVVNSLCIKGDILI--RPILE-----GrALLYSFVSNPEVRI---GVAfggg 240
Cdd:cd21670  76 DLDISYDGD-------ADIEVSVGTGIKAGIKDIQLRGTLRIvlKPLLSelplvG-GVQIFFLNPPEIDFdltGLA---- 143

                       170       180       190
                ....*....|....*....|....*....|....*....
gi 18401863 241 ggqSLPatELPGVSSWLVKILTETLNKKMVEPRRGCFSL 279
Cdd:cd21670 144 ---NLL--DIPGLSNLLRKIIVDQIASFLVLPNRITIPL 177