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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDTYLKGLVKGKSDPYGIIRVGNQIFQSRVIKENLSPKWNEVYEALVYEHPGQELEIELFDEDPD 103
Cdd:cd08391   1 GVLRIHVIEAQDLVAKDKFVGGLVKGKSDPYVIVRVGAQTFKSKVIKENLNPKWNEVYEAVVDEVPGQELEIELFDEDPD 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
4NPJ_B      104 KDDFLGSLMIDLIEVEKERLLDEWFTLDEVPKGKLHLRLEW 144
Cdd:cd08391  81 KDDFLGRLSIDLGSVEKKGFIDEWLPLEDVKSGRLHLKLEW 121

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDTYLKGLVKGKSDPYGIIRVGNQIFQSRVIKENLSPKWNEVYEALVYEHPGQELEIELFDEDPD 103
Cdd:cd08391   1 GVLRIHVIEAQDLVAKDKFVGGLVKGKSDPYVIVRVGAQTFKSKVIKENLNPKWNEVYEAVVDEVPGQELEIELFDEDPD 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
4NPJ_B      104 KDDFLGSLMIDLIEVEKERLLDEWFTLDEVPKGKLHLRLEW 144
Cdd:cd08391  81 KDDFLGRLSIDLGSVEKKGFIDEWLPLEDVKSGRLHLKLEW 121

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B         24 GVLRIHFIEAQDLQGKDtylkglVKGKSDPYGIIRV--GNQIFQSRVIKENLSPKWNEVYEALVYEHPGQELEIELFDED 101
Cdd:pfam00168   1 GRLTVTVIEAKNLPPKD------GNGTSDPYVKVYLldGKQKKKTKVVKNTLNPVWNETFTFSVPDPENAVLEIEVYDYD 74

                          90       100       110
                  ....*....|....*....|....*....|
4NPJ_B        102 -PDKDDFLGSLMIDLIEVEKERLLDEWFTL 130
Cdd:pfam00168  75 rFGRDDFIGEVRIPLSELDSGEGLDGWYPL 104

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B        176 LLILYLDSARNLPSgKKISSNPNPVVQMSVGHKAQ--ESKIRYKTNEPVWEENFTFFIHNPKRQDLEVEVRDE---QHQC 250
Cdd:pfam00168   2 RLTVTVIEAKNLPP-KDGNGTSDPYVKVYLLDGKQkkKTKVVKNTLNPVWNETFTFSVPDPENAVLEIEVYDYdrfGRDD 80

                          90
                  ....*....|....*.
4NPJ_B        251 SLGNLKVPLSQLLTSE 266
Cdd:pfam00168  81 FIGEVRIPLSELDSGE 96

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B        24 GVLRIHFIEAQDLQGKDtylkGLVKGKSDPYGIIRV-GNQIFQSRVIKENLSPKWNEvYEALVYEHPGQELEIELFD-ED 101
Cdd:COG5038  436 GVVEVKIKSAEGLKKSD----STINGTVDPYITVTFsDRVIGKTRVKKNTLNPVWNE-TFYILLNSFTDPLNLSLYDfNS 510

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       102 PDKDDFLGSLMIDLIEVEKERLLDEW---FTLDEVPKGKLHLRLEWLTLMPNASNLDKvltdIKADKDQANDGLSSALLI 178
Cdd:COG5038  511 FKSDKVVGSTQLDLALLHQNPVKKNElyeFLRNTKNVGRLTYDLRFFPVIEDKKELKG----SVEPLEDSNTGILKVTLR 586

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       179 lYLDSARNLPSGKKISSNP---NPVVQMSvghkaqeSKIRYKTNEPVWEENFTFFIHNPKRQDLEVEVRDEQHQCSLGNL 255
Cdd:COG5038  587 -EVKALDELSSKKDNKSAElytNAKEVYS-------TGKLKFTNHPSWNLQYNVLVTDRKNSSIKVVTFDVQSGKVIATE 658

                        250       260       270
                 ....*....|....*....|....*....|..
4NPJ_B       256 KVPLSQLLtSEDMTVSQRFQLSNsgPNSTIKM 287
Cdd:COG5038  659 GSTLPDLI-DRTLDTFLVFPLRN--PKGRIFI 687

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDTYLKGLVKGKSDPYGIIRVGNQIFQSRVIKENLSPKWNEVYEALVYEHPGQELEIELFDEDPD 103
Cdd:cd08391   1 GVLRIHVIEAQDLVAKDKFVGGLVKGKSDPYVIVRVGAQTFKSKVIKENLNPKWNEVYEAVVDEVPGQELEIELFDEDPD 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
4NPJ_B      104 KDDFLGSLMIDLIEVEKERLLDEWFTLDEVPKGKLHLRLEW 144
Cdd:cd08391  81 KDDFLGRLSIDLGSVEKKGFIDEWLPLEDVKSGRLHLKLEW 121

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDTYlkglVKGKSDPYGIIRVGNQIFQSRVIKENLSPKWNEVYEALVYEHPGQELEIELFDEDP- 102
Cdd:cd04024   1 GVLRVHVVEAKDLAAKDRS----GKGKSDPYAILSVGAQRFKTQTIPNTLNPKWNYWCEFPIFSAQNQLLKLILWDKDRf 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
4NPJ_B      103 DKDDFLGSLMIDL---IEVEKERLLDEWFTLD-------EVPKGKLHLRLEW 144
Cdd:cd04024  77 AGKDYLGEFDIALeevFADGKTGQSDKWITLKstrpgktSVVSGEIHLQFSW 128

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       26 LRIHFIEAQDLQGKDTylkglvKGKSDPYGIIRVGN-QIFQSRVIKENLSPKWNEVYEALVYEHPGQELEIELFDEDPD- 103
Cdd:cd00030   1 LRVTVIEARNLPAKDL------NGKSDPYVKVSLGGkQKFKTKVVKNTLNPVWNETFEFPVLDPESDTLTVEVWDKDRFs 74

                        90       100
                ....*....|....*....|....*...
4NPJ_B      104 KDDFLGSLMIDLIEVEKERL-LDEWFTL 130
Cdd:cd00030  75 KDDFLGEVEIPLSELLDSGKeGELWLPL 102

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       25 VLRIHFIEAQDLQGKDtylkglVKGKSDPYGIIRVGNQIFQSRVIKENLSPKWNEVYEALVYEHPGQELEIELFDEDP-D 103
Cdd:cd08376   1 VVTIVLVEGKNLPPMD------DNGLSDPYVKFRLGNEKYKSKVCSKTLNPQWLEQFDLHLFDDQSQILEIEVWDKDTgK 74

                        90       100       110
                ....*....|....*....|....*....|....*..
4NPJ_B      104 KDDFLGSLMIDLIEVEKERLLDEWFTLDEvPKGKLHL 140
Cdd:cd08376  75 KDEFIGRCEIDLSALPREQTHSLELELED-GEGSLLL 110

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDtylkglVKGKSDPYGIIRVGNQIFQSRVIKENLSPKWNEVYE-ALVYEHpgQELEIELFDEDP 102
Cdd:cd08377   1 GFLQVKVIRASGLAAAD------IGGKSDPFCVLELVNARLQTHTIYKTLNPEWNKIFTfPIKDIH--DVLEVTVYDEDK 72

                        90
                ....*....|....*...
4NPJ_B      103 DKD-DFLGSLMIDLIEVE 119
Cdd:cd08377  73 DKKpEFLGKVAIPLLSIK 90

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       26 LRIHFIEAQDLQGKDTylkglvKGKSDPYGIIRV-GNQIFQSRVIKENLSPKWNEVYEALVYEHPGQELEIELFDED-PD 103
Cdd:cd04040   1 LTVDVISAENLPSADR------NGKSDPFVKFYLnGEKVFKTKTIKKTLNPVWNESFEVPVPSRVRAVLKVEVYDWDrGG 74

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
4NPJ_B      104 KDDFLGSLMIDLIEVEKERLLDewFTLDEVPKGKLHLRLEWL 145
Cdd:cd04040  75 KDDLLGSAYIDLSDLEPEETTE--LTLPLDGQGGGKLGAVFL 114

C2 domain present in Arf GTPase Activating Proteins (GAP); ArfGAP is a GTPase activating protein which regulates the ADP ribosylation factor Arf, a member of the Ras superfamily of GTP-binding proteins. The GTP-bound form of Arf is involved in Golgi morphology and is involved in recruiting coat proteins. ArfGAP is responsible for the GDP-bound form of Arf which is necessary for uncoating the membrane and allowing the Golgi to fuse with an acceptor compartment. These proteins contain an N-terminal ArfGAP domain containing the characteristic zinc finger motif (Cys-x2-Cys-x(16,17)-x2-Cys) and C-terminal C2 domain. C2 domains were first identified in Protein Kinase C (PKC). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDTylkglvkGKSDPYGIIRVGNQIFQSRVIKENLSPKWNEVYeALVYEHPGQELEIELFDED-P 102
Cdd:cd04038   2 GLLKVRVVRGTNLAVRDF-------TSSDPYVVLTLGNQKVKTRVIKKNLNPVWNEEL-TLSVPNPMAPLKLEVFDKDtF 73

                        90
                ....*....|...
4NPJ_B      103 DKDDFLGSLMIDL 115
Cdd:cd04038  74 SKDDSMGEAEIDL 86

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDTylkglVKGKSDPY---GIIRVGNQIFQSRVIKENLSPKWNEvyEALVYEHP-----GQELEI 95
Cdd:cd04041   1 GVLVVTIHRATDLPKADF-----GTGSSDPYvtaSFAKFGKPLYSTRIIRKDLNPVWEE--TWFVLVTPdevkaGERLSC 73

                        90       100
                ....*....|....*....|.
4NPJ_B       96 ELFDED-PDKDDFLGSLMIDL 115
Cdd:cd04041  74 RLWDSDrFTADDRLGRVEIDL 94

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B      177 LILYLDSARNLPSgKKISSNPNPVVQMSVGHKA-QESKIRYKTNEPVWEENFTFFIHNPKRQDLEVEVRDE---QHQCSL 252
Cdd:cd00030   1 LRVTVIEARNLPA-KDLNGKSDPYVKVSLGGKQkFKTKVVKNTLNPVWNETFEFPVLDPESDTLTVEVWDKdrfSKDDFL 79

                        90
                ....*....|.
4NPJ_B      253 GNLKVPLSQLL 263
Cdd:cd00030  80 GEVEIPLSELL 90

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B        176 LLILYLDSARNLPSgKKISSNPNPVVQMSVGHKAQ--ESKIRYKTNEPVWEENFTFFIHNPKRQDLEVEVRDE---QHQC 250
Cdd:pfam00168   2 RLTVTVIEAKNLPP-KDGNGTSDPYVKVYLLDGKQkkKTKVVKNTLNPVWNETFTFSVPDPENAVLEIEVYDYdrfGRDD 80

                          90
                  ....*....|....*.
4NPJ_B        251 SLGNLKVPLSQLLTSE 266
Cdd:pfam00168  81 FIGEVRIPLSELDSGE 96

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDTYlkglvkGKSDPYGIIRVGNQIFQSRVI-KENLSPKWNEVYEALVYEHPGQELEIELFDEDP 102
Cdd:cd08681   1 GTLVVVVLKARNLPNKRKL------DKQDPYCVLRIGGVTKKTKTDfRGGQHPEWDEELRFEITEDKKPILKVAVFDDDK 74

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
4NPJ_B      103 DKDDFLGSLMIDLIEVEKERLLDEWFTL--DEVPKGKLHLRL 142
Cdd:cd08681  75 RKPDLIGDTEVDLSPALKEGEFDDWYELtlKGRYAGEVYLEL 116

C2 domain in Protein Kinase C (PKC) epsilon; A single C2 domain is found in PKC epsilon. 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-II topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDTYLKGLVKGKS----DPYGIIRVGNQIF-QSRVIKENLSPKWNEVYEALVyeHPGQELEIELF 98
Cdd:cd04014   4 GTLKIKICEAVDLKPTDWSTRHAVPKKGsqllDPYVSIDVDDTHIgKTSTKPKTNSPVWNEEFTTEV--HNGRNLELTVF 81

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
4NPJ_B       99 -DEDPDKDDFLGSLMI---DLIEVEKERLlDEWFTLDevPKGKLHLRLEW 144
Cdd:cd04014  82 hDAAIGPDDFVANCTIsfeDLIQRGSGSF-DLWVDLE--PQGKLHVKIEL 128

C2 domain fifth repeat in Ferlin; Ferlins are involved in vesicle fusion events. Ferlins and other proteins, such as Synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1). Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the fifth C2 repeat, C2E, and has a type-II topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       25 VLRIHFIEAQDLQGKDtylkglVKGKSDPYGIIRVGNQIFQSR--VIKENLSPKWNEVYEaLVYEHPG-QELEIELFDED 101
Cdd:cd04037   1 LVRVYVVRARNLQPKD------PNGKSDPYLKIKLGKKKINDRdnYIPNTLNPVFGKMFE-LEATLPGnSILKISVMDYD 73

                        90
                ....*....|....*
4NPJ_B      102 P-DKDDFLGSLMIDL 115
Cdd:cd04037  74 LlGSDDLIGETVIDL 88

C2 domain present in the Human neural precursor cell-expressed, developmentally down-regulated 4 (NEDD4) and NEDD4-like (NEDD4L/NEDD42); Nedd4 and Nedd4-2 are two of the nine members of the Human Nedd4 family. All vertebrates appear to have both Nedd4 and Nedd4-2 genes. They are thought to participate in the regulation of epithelial Na+ channel (ENaC) activity. They also have identical specificity for ubiquitin conjugating enzymes (E2). Nedd4 and Nedd4-2 are composed of a C2 domain, 2-4 WW domains, and a ubiquitin ligase Hect domain. Their WW domains can bind PPxY (PY) or LPSY motifs, and in vitro studies suggest that WW3 and WW4 of both proteins bind PY motifs in the key substrates, with WW3 generally exhibiting higher affinity. Most Nedd4 family members, especially Nedd4-2, also have multiple splice variants, which might play different roles in regulating their substrates. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       25 VLRIHFIEAQDLQGKDTYlkglvkGKSDPYGIIRV-----GNQI--FQSRVIKENLSPKWNEVYEALVyeHPGQ-ELEIE 96
Cdd:cd04033   1 ILRVKVLAGIDLAKKDIF------GASDPYVKISLydpdgNGEIdsVQTKTIKKTLNPKWNEEFFFRV--NPREhRLLFE 72

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
4NPJ_B       97 LFDEDP-DKDDFLGSLMIDLI------EVEKERLLDEWFTLDEVP-----KGKLHLRLEWL 145
Cdd:cd04033  73 VFDENRlTRDDFLGQVEVPLNnlptetPGNERRYTFKDYLLRPRSsksrvKGHLRLYMAYL 133

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       24 GVLRIHFIEAQDLQGKDTylkglvKGKS-DPYGIIRVGNQ--IFQSRVIKENLSPKWNEVYEALVYEHpGQELEIELFDE 100
Cdd:cd04044   2 GVLAVTIKSARGLKGSDI------IGGTvDPYVTFSISNRreLARTKVKKDTSNPVWNETKYILVNSL-TEPLNLTVYDF 74

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
4NPJ_B      101 DPDKDD-FLGSLMIDLIEVEKERLLDE---WFTLDEVPKGKLHLRLEW 144
Cdd:cd04044  75 NDKRKDkLIGTAEFDLSSLLQNPEQENltkNLLRNGKPVGELNYDLRF 122

C2 domain second repeat in Munc13 (mammalian uncoordinated) proteins; C2-like domains are thought to be involved in phospholipid binding in a Ca2+ independent manner in both Unc13 and Munc13. Caenorabditis elegans Unc13 has a central domain with sequence similarity to PKC, which includes C1 and C2-related domains. Unc13 binds phorbol esters and DAG with high affinity in a phospholipid manner. Mutations in Unc13 results in abnormal neuronal connections and impairment in cholinergic neurotransmission in the nematode. Munc13 is the mammalian homolog which are expressed in the brain. There are 3 isoforms (Munc13-1, -2, -3) and are thought to play a role in neurotransmitter release and are hypothesized to be high-affinity receptors for phorbol esters. Unc13 and Munc13 contain both C1 and C2 domains. There are two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. Munc13 interacts with syntaxin, synaptobrevin, and synaptotagmin suggesting a role for these as scaffolding proteins. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       26 LRIHFIEAQDLQGKDTylkglvKGKSDPYGIIRVGNQIFQSRVIKENLSPKWNEVYealVYE--HPGQELEIELFDEDPD 103
Cdd:cd04027   3 ISITVVCAQGLIAKDK------TGTSDPYVTVQVGKTKKRTKTIPQNLNPVWNEKF---HFEchNSSDRIKVRVWDEDDD 73

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
4NPJ_B      104 ------------KDDFLGSLMIDLIEVEKErlLDEWFTLDE 132
Cdd:cd04027  74 iksrlkqkftreSDDFLGQTIIEVRTLSGE--MDVWYNLEK 112

C2 domain fourth repeat in Ferlin; Ferlins are involved in vesicle fusion events. Ferlins and other proteins, such as Synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1). Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the fourth C2 repeat, C2D, and has a type-II topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       26 LRIHFIEAQDLQGKDTylkglvKGKSDPYgiIRV--GNQIFQSRVIKENLSPKWNEV---YEALVYEHPGQELE------ 94
Cdd:cd04017   3 LRAYIYQARDLLAADK------SGLSDPF--ARVsfLNQSQETEVIKETLSPTWDQTlifDEVELYGSPEEIAQnpplvv 74

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
4NPJ_B       95 IELFDEDPD-KDDFLGSLMIdlieVEKERLLDEWftlDEVPKgklhlrLEWLTLM 148
Cdd:cd04017  75 VELFDQDSVgKDEFLGRSVA----KPLVKLDLEE---DFPPK------LQWFPIY 116

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B       26 LRIHFIEAQDLQGKDtylKGLVKgksDPYGIIRVGNQIFQSRVIK-ENLSPKWNEVYEALVYEHPGQELEIELFD-EDPD 103
Cdd:cd04019   2 LRVTVIEAQDLVPSD---KNRVP---EVFVKAQLGNQVLRTRPSQtRNGNPSWNEELMFVAAEPFEDHLILSVEDrVGPN 75

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
4NPJ_B      104 KDDFLGSLMIDLIEVEKeRLLDE-----WFTL----------DEVP-KGKLHLRL 142
Cdd:cd04019  76 KDEPLGRAVIPLNDIER-RVDDRpvpsrWFSLerpggameqkKKRKfASRIHLRL 129

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B      183 SARNL-PSGKKISSNPNPVVQMSvGHKaQESKIRYKTNEPVWEENFTFFIHNPKR---QDLEVEV----RDEQHQCSLGN 254
Cdd:cd04022   8 DAQDLmPKDGQGSSSAYVELDFD-GQK-KRTRTKPKDLNPVWNEKLVFNVSDPSRlsnLVLEVYVyndrRSGRRRSFLGR 85

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
4NPJ_B      255 LKVPLSQLLtSEDMTVSQRFQLSNSGPNSTIKMKIALRVL 294
Cdd:cd04022  86 VRISGTSFV-PPSEAVVQRYPLEKRGLFSRVRGEIGLKVY 124

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
4NPJ_B      184 ARNLPSGkkissNPNPVVQMSVGHKAQESKIRYKTNEPVWEENFTFFIHNPK 235
Cdd:cd04011  13 ARQLVGG-----NIDPVVKVEVGGQKKYTSVKKGTNCPFYNEYFFFNFHESP 59

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B        10 SEVQIAQLRFPVPK-----------GVLRIHFIEAQDLQGKDTylkglvKGKSDPYGIIRV-GNQIFQSRVIKENLSPKW 77
Cdd:COG5038 1015 AKVLVQVSYTPVPVklppvemvensGYLTIMLRSGENLPSSDE------NGYSDPFVKLFLnEKSVYKTKVVKKTLNPVW 1088

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
4NPJ_B        78 NEVYEALVYEHPGQELEIELFDEDPD-KDDFLGSLMIDL--IEVEKERLLDEWFTLDEVPKGKLHLRLEWlTLMP----N 150
Cdd:COG5038 1089 NEEFTIEVLNRVKDVLTINVNDWDSGeKNDLLGTAEIDLskLEPGGTTNSNIPLDGKTFIVLDGTLHPGF-NFRSkyalN 1167

                        170
                 ....*....|.
4NPJ_B       151 ASNLDKVLTDI 161
Cdd:COG5038 1168 VSRKEGILGDI 1178

C2 domain present in Smad ubiquitination-related factor (Smurf)-like proteins; A single C2 domain is found in Smurf proteins, C2-WW-HECT-domain E3s, which play an important role in the downregulation of the TGF-beta signaling pathway. Smurf proteins also regulate cell shape, motility, and polarity by degrading small guanosine triphosphatases (GTPases). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have type-II topology.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
4NPJ_B       52 DPYGIIRV-GNQIFQSRVIKENLSPKWNEVYEalVYEHPGQELEIELFDE---DPDKDDFLG 109
Cdd:cd08382  22 DPFAVITVdGGQTHSTDVAKKTLDPKWNEHFD--LTVGPSSIITIQVFDQkkfKKKDQGFLG 81