C2 domain found in Rab11-family interacting proteins (FIP) class I; Rab GTPases recruit various effector proteins to organelles and vesicles. Rab11-family interacting proteins (FIPs) are involved in mediating the role of Rab11. FIPs can be divided into three classes: class I FIPs (Rip11a, Rip11b, RCP, and FIP2) which contain a C2 domain after N-terminus of the protein, class II FIPs (FIP3 and FIP4) which contain two EF-hands and a proline rich region, and class III FIPs (FIP1) which exhibits no homology to known protein domains. All FIP proteins contain a highly conserved, 20-amino acid motif at the C-terminus of the protein, known as Rab11/25 binding domain (RBD). Class I FIPs are thought to bind to endocytic membranes via their C2 domain, which interacts directly with phospholipids. Class II FIPs do not have any membrane binding domains leaving much to speculate about the mechanism involving FIP3 and FIP4 interactions with endocytic membranes. The members in this CD are class I FIPs. The exact function of the Rab11 and FIP interaction is unknown, but there is speculation that it involves the role of forming a targeting complex that recruits a group of proteins involved in membrane transport to organelles. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   20 VQVTVLQARGLRAKGPGGTSDAYAVIQVGKEKYATSVSERSLgAPVWREEATFELPSLLSsGPAAAATLQLTVLHRALLG 99
Cdd:cd08682     1 VQVTVLQARGLLCKGKSGTNDAYVIIQLGKEKYSTSVKEKTT-SPVWKEECSFELPGLLS-GNGNRATLQLTVMHRNLLG 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 289547524  100 LDKFLGRAEVDLRDLHRDQGRRKTQWYKLKSKPGKKDKERGEIEVDIQ 147
Cdd:cd08682    79 LDKFLGQVSIPLNDLDEDKGRRRTRWFKLESKPGKDDKERGEIEVDIQ 126

C2 domain found in Rab11-family interacting proteins (FIP) class I; Rab GTPases recruit various effector proteins to organelles and vesicles. Rab11-family interacting proteins (FIPs) are involved in mediating the role of Rab11. FIPs can be divided into three classes: class I FIPs (Rip11a, Rip11b, RCP, and FIP2) which contain a C2 domain after N-terminus of the protein, class II FIPs (FIP3 and FIP4) which contain two EF-hands and a proline rich region, and class III FIPs (FIP1) which exhibits no homology to known protein domains. All FIP proteins contain a highly conserved, 20-amino acid motif at the C-terminus of the protein, known as Rab11/25 binding domain (RBD). Class I FIPs are thought to bind to endocytic membranes via their C2 domain, which interacts directly with phospholipids. Class II FIPs do not have any membrane binding domains leaving much to speculate about the mechanism involving FIP3 and FIP4 interactions with endocytic membranes. The members in this CD are class I FIPs. The exact function of the Rab11 and FIP interaction is unknown, but there is speculation that it involves the role of forming a targeting complex that recruits a group of proteins involved in membrane transport to organelles. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   20 VQVTVLQARGLRAKGPGGTSDAYAVIQVGKEKYATSVSERSLgAPVWREEATFELPSLLSsGPAAAATLQLTVLHRALLG 99
Cdd:cd08682     1 VQVTVLQARGLLCKGKSGTNDAYVIIQLGKEKYSTSVKEKTT-SPVWKEECSFELPGLLS-GNGNRATLQLTVMHRNLLG 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 289547524  100 LDKFLGRAEVDLRDLHRDQGRRKTQWYKLKSKPGKKDKERGEIEVDIQ 147
Cdd:cd08682    79 LDKFLGQVSIPLNDLDEDKGRRRTRWFKLESKPGKDDKERGEIEVDIQ 126

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 289547524     22 VTVLQARGLRAKGPGGTSDAYAVIQVG---KEKYATSVSERSLgAPVWREEATFELPsllssgPAAAATLQLTVLHRALL 98
Cdd:smart00239    4 VKIISARNLPPKDKGGKSDPYVKVSLDgdpKEKKKTKVVKNTL-NPVWNETFEFEVP------PPELAELEIEVYDKDRF 76

                            90       100
                    ....*....|....*....|....
gi 289547524     99 GLDKFLGRAEVDLRDLHRDQGRRK 122
Cdd:smart00239   77 GRDDFIGQVTIPLSDLLLGGRHEK 100

C2 domain found in Rab11-family interacting proteins (FIP) class I; Rab GTPases recruit various effector proteins to organelles and vesicles. Rab11-family interacting proteins (FIPs) are involved in mediating the role of Rab11. FIPs can be divided into three classes: class I FIPs (Rip11a, Rip11b, RCP, and FIP2) which contain a C2 domain after N-terminus of the protein, class II FIPs (FIP3 and FIP4) which contain two EF-hands and a proline rich region, and class III FIPs (FIP1) which exhibits no homology to known protein domains. All FIP proteins contain a highly conserved, 20-amino acid motif at the C-terminus of the protein, known as Rab11/25 binding domain (RBD). Class I FIPs are thought to bind to endocytic membranes via their C2 domain, which interacts directly with phospholipids. Class II FIPs do not have any membrane binding domains leaving much to speculate about the mechanism involving FIP3 and FIP4 interactions with endocytic membranes. The members in this CD are class I FIPs. The exact function of the Rab11 and FIP interaction is unknown, but there is speculation that it involves the role of forming a targeting complex that recruits a group of proteins involved in membrane transport to organelles. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   20 VQVTVLQARGLRAKGPGGTSDAYAVIQVGKEKYATSVSERSLgAPVWREEATFELPSLLSsGPAAAATLQLTVLHRALLG 99
Cdd:cd08682     1 VQVTVLQARGLLCKGKSGTNDAYVIIQLGKEKYSTSVKEKTT-SPVWKEECSFELPGLLS-GNGNRATLQLTVMHRNLLG 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 289547524  100 LDKFLGRAEVDLRDLHRDQGRRKTQWYKLKSKPGKKDKERGEIEVDIQ 147
Cdd:cd08682    79 LDKFLGQVSIPLNDLDEDKGRRRTRWFKLESKPGKDDKERGEIEVDIQ 126

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   20 VQVTVLQARGLRAKGPGGTSDAYAVIQVG-KEKYATSVSERSLgAPVWREEATFELPSLLSSgpaaaaTLQLTVLHRALL 98
Cdd:cd00030     1 LRVTVIEARNLPAKDLNGKSDPYVKVSLGgKQKFKTKVVKNTL-NPVWNETFEFPVLDPESD------TLTVEVWDKDRF 73

                          90       100       110
                  ....*....|....*....|....*....|
gi 289547524   99 GLDKFLGRAEVDLRDLhRDQGRRKTQWYKL 128
Cdd:cd00030    74 SKDDFLGEVEIPLSEL-LDSGKEGELWLPL 102

FIP domain; The FIP domain is the Rab11-binding domain (RBD) at the C-terminus of a family of Rab11-interacting proteins (FIPs). The Rab proteins constitute the largest family of small GTPases (>60 members in mammals). Among them Rab11 is a well characterized regulator of endocytic and recycling pathways. Rab11 associates with a broad range of post-Golgi organelles, including recycling endosomes.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 289547524  1226 THDELIQLVLKQKETIskkefqvRELEDYIDNLLVRVMEETPNILRIP 1273
Cdd:pfam09457    1 SRDELQDALQKQEEEN-------RRLEDYIDNILLRIMEHNPSILEVP 41

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   19 HVQVTVLQARGLRAKGPGGTSDAY---AVIQVGKE--KYATSVSeRSLGAPVWREEATFELPSLLSSGpaaaATLQLTVL 93
Cdd:cd00276    15 RLTVVVLKARNLPPSDGKGLSDPYvkvSLLQGGKKlkKKKTSVK-KGTLNPVFNEAFSFDVPAEQLEE----VSLVITVV 89

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 289547524   94 HRALLGLDKFLGRAEVDLrdlhRDQGRRKTQWYKLKSKPGK 134
Cdd:cd00276    90 DKDSVGRNEVIGQVVLGP----DSGGEELEHWNEMLASPRK 126

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   20 VQVTVLQARGLRAKGPGgTSDAYAVIQVGKEKYATSVSERSLGaPVWREEATFELPSLlssgpaaAATLQLTVLHRALLG 99
Cdd:cd04038     4 LKVRVVRGTNLAVRDFT-SSDPYVVLTLGNQKVKTRVIKKNLN-PVWNEELTLSVPNP-------MAPLKLEVFDKDTFS 74

                          90
                  ....*....|....*
gi 289547524  100 LDKFLGRAEVDLRDL 114
Cdd:cd04038    75 KDDSMGEAEIDLEPL 89

C2 domain found in the Human chromosome 21 open reading frame 25 (C21orf25) protein; The members in this cd are named after the Human C21orf25 which contains a single C2 domain. Several other members contain a C1 domain downstream of the C2 domain. No other information on this protein is currently known. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   22 VTVLQARGLraKGPGGTSDAYAVIQVGK--EKYATSVSeRSLGAPVWREEATFELPsllssgpAAAATLQLTVLHRALLG 99
Cdd:cd08678     3 VKNIKANGL--SEAAGSSNPYCVLEMDEppQKYQSSTQ-KNTSNPFWDEHFLFELS-------PNSKELLFEVYDNGKKS 72

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 289547524  100 LDKFLGRAEVDLRDLHRDQGRRktQWYKLKSKPGKKDKERGEIEVDIQFM 149
Cdd:cd08678    73 DSKFLGLAIVPFDELRKNPSGR--QIFPLQGRPYEGDSVSGSITVEFLFM 120

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 289547524   20 VQVTVLQARGLRAK------GPGGTSDAYAVIQVGKEKYATSVSERSLGaPVWREeaTFElpSLLSSGPaaaaTLQLTV- 92
Cdd:cd08391     3 LRIHVIEAQDLVAKdkfvggLVKGKSDPYVIVRVGAQTFKSKVIKENLN-PKWNE--VYE--AVVDEVP----GQELEIe 73

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 289547524   93 LHRALLGLDKFLGRAEVDLRDLHRDqgRRKTQWYKLKS 130
Cdd:cd08391    74 LFDEDPDKDDFLGRLSIDLGSVEKK--GFIDEWLPLED 109

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 289547524   22 VTVLQARGLRAKGPGGTSDAYAVIQV--GKEK---YATSVSERSLGaPVWREeaTFELPslLSSGPAAAATLQLTVL-HR 95
Cdd:cd04030    20 VTVHKCRNLPPCDSSDIPDPYVRLYLlpDKSKstrRKTSVKKDNLN-PVFDE--TFEFP--VSLEELKRRTLDVAVKnSK 94

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 289547524   96 ALLGLDK-FLGRAEVDLRDLhrDQGRRKTQWYKLK 129
Cdd:cd04030    95 SFLSREKkLLGQVLIDLSDL--DLSKGFTQWYDLT 127

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 289547524   22 VTVLQARGLRAKGPGGTSDAYAVIQV-GKEKYATSVSERSLGaPVWREEATFELPSLLssgpaaAATLQLTVLHRALLGL 100
Cdd:cd04040     3 VDVISAENLPSADRNGKSDPFVKFYLnGEKVFKTKTIKKTLN-PVWNESFEVPVPSRV------RAVLKVEVYDWDRGGK 75

                          90
                  ....*....|....
gi 289547524  101 DKFLGRAEVDLRDL 114
Cdd:cd04040    76 DDLLGSAYIDLSDL 89

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
                  ....*....|....*....|....*....|....*....|....*....|....
gi 289547524   20 VQVTVLQARGLRAKGPGGTSDAYAVIQVGKEKYATSVSERSLGaPVWREEATFE 73
Cdd:cd04027     3 ISITVVCAQGLIAKDKTGTSDPYVTVQVGKTKKRTKTIPQNLN-PVWNEKFHFE 55

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   22 VTVLQARGLrakgPGGTSDAYAVIQVGKEKYATSVSERSLgAPVWREEATFELPSLLSSgpaaaaTLQLTVlHRALLGLD 101
Cdd:cd08378     4 VRVVKARGL----PANSNDPVVEVKLGNYKGSTKAIERTS-NPEWNQVFAFSKDRLQGS------TLEVSV-WDKDKAKD 71

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 289547524  102 KFLGRAEVDLRDLH-RDQ--GRRKTQWYKLKSKPGKKDkeRGEIEVDIQF 148
Cdd:cd08378    72 DFLGGVCFDLSEVPtRVPpdSPLAPQWYRLEDKKGGRV--GGELMLAVWF 119

C2 domain first repeat present in Synaptotagmin-like proteins 1 and 2; All Slp members basically share an N-terminal Slp homology domain (SHD) and C-terminal tandem C2 domains (named the C2A domain and the C2B domain) with the SHD and C2 domains being separated by a linker sequence of various length. Slp1/JFC1 and Slp2/exophilin 4 promote granule docking to the plasma membrane. Additionally, their C2A domains are both Ca2+ independent, unlike Slp3 and Slp4/granuphilin which are Ca2+ dependent. It is thought that SHD (except for the Slp4-SHD) functions as a specific Rab27A/B-binding domain. In addition to Slps, rabphilin, Noc2, and Munc13-4 also function as Rab27-binding proteins. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   21 QVTVLQARGLRAKGP-GGTSDAYAVI-------QVGKEKyaTSVSERSLGaPVWREEATF-----ELPSllssgpaaaAT 87
Cdd:cd08393    18 HVHVIQCQDLAAADPkKQRSDPYVKTyllpdksNRGKRK--TSVKKKTLN-PVFNETLRYkvereELPT---------RV 85

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 289547524   88 LQLTVLHRALLGLDKFLGRAEVDLRDLhrDQGRRKTQWYKLK 129
Cdd:cd08393    86 LNLSVWHRDSLGRNSFLGEVEVDLGSW--DWSNTQPTWYPLQ 125

C2 domain first repeat contained in Rab3-interacting molecule (RIM) proteins; RIMs are believed to organize specialized sites of the plasma membrane called active zones. They also play a role in controlling neurotransmitter release, plasticity processes, as well as memory and learning. RIM contains an N-terminal zinc finger domain, a PDZ domain, and two C-terminal C2 domains (C2A, C2B). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have a type-I topology and do not bind Ca2+.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   22 VTVLQARGLRAKGPGGTSDAYAVI-----QVGKEKYATSVSERSLgAPVWreEATFELPS-----LLSSgpaaaaTLQLT 91
Cdd:cd04031    20 VTVLQARDLPPRDDGSLRNPYVKVyllpdRSEKSKRRTKTVKKTL-NPEW--NQTFEYSNvrretLKER------TLEVT 90

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 289547524   92 VLHRALLGLDKFLGRAEVDLRDLHRDQgrrKTQWYKLK 129
Cdd:cd04031    91 VWDYDRDGENDFLGEVVIDLADALLDD---EPHWYPLQ 125

C2 domain first repeat present in Synaptotagmin-like proteins; All Slp members basically share an N-terminal Slp homology domain (SHD) and C-terminal tandem C2 domains (named the C2A domain and the C2B domain) with the SHD and C2 domains being separated by a linker sequence of various length. Slp1/JFC1 and Slp2/exophilin 4 promote granule docking to the plasma membrane. Additionally, their C2A domains are both Ca2+ independent, unlike the case in Slp3 and Slp4/granuphilin in which their C2A domains are Ca2+ dependent. It is thought that SHD (except for the Slp4-SHD) functions as a specific Rab27A/B-binding domain. In addition to Slps, rabphilin, Noc2, and Munc13-4 also function as Rab27-binding proteins. It has been demonstrated that Slp3 and Slp4/granuphilin promote dense-core vesicle exocytosis. Slp5 mRNA has been shown to be restricted to human placenta and liver suggesting a role in Rab27A-dependent membrane trafficking in specific tissues. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   48 GKEKyaTSVSERSLGaPVWREEATFELP-SLLSSgpaaaATLQLTVLHRALLGLDKFLGraEVDLRDLHRDQGRRKTQWY 126
Cdd:cd08521    52 SKRK--TSVKKNTTN-PVFNETLKYHISkSQLET-----RTLQLSVWHHDRFGRNTFLG--EVEIPLDSWDLDSQQSEWY 121

                  ..
gi 289547524  127 KL 128
Cdd:cd08521   122 PL 123

C2 domain fourth 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 fourth C2 repeat, C2D, and has a type-II topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   19 HVQVTVLQARG---LRAKGPGGTSDAYAVIQVGKEKYATSVSERSLgAPVWREEATFELPSllSSGPAAAATLQLTVLH- 94
Cdd:cd08379     1 ILEVGILGAQGldvLRAKDGRGSTDAYCVAKYGPKWVRTRTVEDSS-NPRWNEQYTWPVYD--PCTVLTVGVFDNSQSHw 77

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 289547524   95 RALLGLDKFLGRaeVDLRDLHRDQGRRKTQWYKLKSKPGKKDKERGEIEV 144
Cdd:cd08379    78 KEAVQPDVLIGK--VRIRLSTLEDDRVYAHSYPLLSLNPSGVKKMGELEC 125

C2 domain found in the Human KIAA0528 cDNA clone; The members of this CD are named after the Human KIAA0528 cDNA clone. All members here contain a single C2 repeat. No other information on this protein is currently known. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   20 VQVTVLQARGL----RAKGpggTSDAYAVIQVGKEKYATSVSERSLGaPVWREEA-TFELPS-LLSSGPaaaatLQLTVL 93
Cdd:cd08688     1 LKVRVVAARDLpvmdRSSD---LTDAFVEVKFGSTTYKTDVVKKSLN-PVWNSEWfRFEVDDeELQDEP-----LQIRVM 71

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 289547524   94 HRALLGLDKFLGRAEVDLRDL-HRDQGRRKTQWYKL 128
Cdd:cd08688    72 DHDTYSANDAIGKVYIDLNPLlLKDSVSQISGWFPI 107

C2 domain in Munc13 (mammalian uncoordinated) proteins; fungal group; 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   22 VTVLQARGLRAKGPGGTSDAYAVI---QVGKEKYATSVSERSLGaPVWREEatFELPSllssGPAAAATLQLTVLHRALL 98
Cdd:cd04043     5 IRIVRAENLKADSSNGLSDPYVTLvdtNGKRRIAKTRTIYDTLN-PRWDEE--FELEV----PAGEPLWISATVWDRSFV 77

                          90
                  ....*....|...
gi 289547524   99 GLDKFLGRAEVDL 111
Cdd:cd04043    78 GKHDLCGRASLKL 90

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   20 VQVTVLQARGLrakgPGGTSDAYAVIQVGKEKYATSVSERSLgAPVWREEATF---ELPSLLSSGPaaaatLQLTVLHRA 96
Cdd:cd04011     6 VRVRVIEARQL----VGGNIDPVVKVEVGGQKKYTSVKKGTN-CPFYNEYFFFnfhESPDELFDKI-----IKISVYDSR 75

                          90
                  ....*....|....*
gi 289547524   97 LLGLDKFLGRAEVDL 111
Cdd:cd04011    76 SLRSDTLIGSFKLDV 90

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 289547524   22 VTVLQARGLRAKGPGGTSDAYAVIQV---GK--EKYATSVSERSLGaPVWREEATFELPsllsSGPAAAATLQLTVLHRA 96
Cdd:cd08405    19 VNIIKARNLKAMDINGTSDPYVKVWLmykDKrvEKKKTVIKKRTLN-PVFNESFIFNIP----LERLRETTLIITVMDKD 93

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 289547524   97 LLGLDKFLGRAEVDlrdlHRDQGRRKTQWYKLKSKPGK 134
Cdd:cd08405    94 RLSRNDLIGKIYLG----WKSGGLELKHWKDMLSKPRQ 127

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   20 VQVTVLQARGLR-AKGPGGTSDAYAVIQ---VGKEKYATSVSERSLGaPVWREEATfelpsLLSSGPAAAATLQLTVlhr 95
Cdd:cd04041     3 LVVTIHRATDLPkADFGTGSSDPYVTASfakFGKPLYSTRIIRKDLN-PVWEETWF-----VLVTPDEVKAGERLSC--- 73

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 289547524   96 ALLGLDKF-----LGRAEVDLRDL--HRDQGRRKTQ 124
Cdd:cd04041    74 RLWDSDRFtaddrLGRVEIDLKELieDRNWMGRRED 109

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 289547524   20 VQVTVLQARGLR----AKGPGGTS------DAYAVIQVGKEKYA-TSVSERSLgAPVWREEATFELPSllssgpaaAATL 88
Cdd:cd04014     6 LKIKICEAVDLKptdwSTRHAVPKkgsqllDPYVSIDVDDTHIGkTSTKPKTN-SPVWNEEFTTEVHN--------GRNL 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 289547524   89 QLTVLHRALLGLDKFLGRAEVDLRDLHRDQGRRKTQWYKL 128
Cdd:cd04014    77 ELTVFHDAAIGPDDFVANCTISFEDLIQRGSGSFDLWVDL 116