C2 domain found in Human protein Kibra; Kibra is thought to be a regulator of the Salvador (Sav)/Warts (Wts)/Hippo (Hpo) (SWH) signaling network, which limits tissue growth by inhibiting cell proliferation and promoting apoptosis. The core of the pathway consists of a MST and LATS family kinase cascade that ultimately phosphorylates and inactivates the YAP/Yorkie (Yki) transcription coactivator. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are part of the upstream regulation controlling pathway mechanism. Kibra colocalizes and associates with Mer and Ex and is thought to transduce an extracellular signal via the SWH network. The apical scaffold machinery that contains Hpo, Wts, and Ex recruits Yki to the apical membrane facilitating its inhibitory phosphorlyation by Wts. Since Kibra associates with Ex and is apically located it is hypothesized that KIBRA is part of the scaffold, helps in the Hpo/Wts complex, and helps recruit Yki for inactivation that promotes SWH pathway activity. Kibra contains two amino-terminal WW domains, an internal C2-like domain, and a carboxy-terminal glutamic acid-rich stretch. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665394080  693 AQVQIGLKYLKQEGVLVVSLERANNLLALwtASADNSQVYLRAALLP---NSLTSIRTKALGDFQKPVFNDTFAVPITLD 769
Cdd:cd08680     1 AQVQIGLRYDSGDSSLVISVEQLRNLSAL--SIPENSKVYVRVALLPcssSTSCLFRTKALEDQDKPVFNEVFRVPISST 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 665394080  770 KLLTKSLQVTVVTMTG-QKEEIIGTVQISMAEF-NPEDSTLKWYNV 813
Cdd:cd08680    79 KLYQKTLQVDVCSVGPdQQEECLGGAQISLADFeSSEEMSTKWYNL 124

WW domain; The WW domain is a protein module with two highly conserved tryptophans that binds proline-rich peptide motifs in vitro.

                           10        20        30
                   ....*....|....*....|....*....|
gi 665394080   103 LPMGWEESYDPNIGPYYINHLAQSTQLEDP 132
Cdd:pfam00397    1 LPPGWEERWDPDGRVYYYNHETGETQWEKP 30

C2 domain found in Human protein Kibra; Kibra is thought to be a regulator of the Salvador (Sav)/Warts (Wts)/Hippo (Hpo) (SWH) signaling network, which limits tissue growth by inhibiting cell proliferation and promoting apoptosis. The core of the pathway consists of a MST and LATS family kinase cascade that ultimately phosphorylates and inactivates the YAP/Yorkie (Yki) transcription coactivator. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are part of the upstream regulation controlling pathway mechanism. Kibra colocalizes and associates with Mer and Ex and is thought to transduce an extracellular signal via the SWH network. The apical scaffold machinery that contains Hpo, Wts, and Ex recruits Yki to the apical membrane facilitating its inhibitory phosphorlyation by Wts. Since Kibra associates with Ex and is apically located it is hypothesized that KIBRA is part of the scaffold, helps in the Hpo/Wts complex, and helps recruit Yki for inactivation that promotes SWH pathway activity. Kibra contains two amino-terminal WW domains, an internal C2-like domain, and a carboxy-terminal glutamic acid-rich stretch. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665394080  693 AQVQIGLKYLKQEGVLVVSLERANNLLALwtASADNSQVYLRAALLP---NSLTSIRTKALGDFQKPVFNDTFAVPITLD 769
Cdd:cd08680     1 AQVQIGLRYDSGDSSLVISVEQLRNLSAL--SIPENSKVYVRVALLPcssSTSCLFRTKALEDQDKPVFNEVFRVPISST 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 665394080  770 KLLTKSLQVTVVTMTG-QKEEIIGTVQISMAEF-NPEDSTLKWYNV 813
Cdd:cd08680    79 KLYQKTLQVDVCSVGPdQQEECLGGAQISLADFeSSEEMSTKWYNL 124

Domain with 2 conserved Trp (W) residues; Also known as the WWP or rsp5 domain. Binds proline-rich polypeptides.

                            10        20        30
                    ....*....|....*....|....*....|...
gi 665394080     55 PLPDGWDIAKDFDGKTYYIDHINKKTTWLDPRD 87
Cdd:smart00456    1 PLPPGWEERKDPDGRPYYYNHETKETQWEKPRE 33

WW domain; The WW domain is a protein module with two highly conserved tryptophans that binds proline-rich peptide motifs in vitro.

                           10        20        30
                   ....*....|....*....|....*....|
gi 665394080   103 LPMGWEESYDPNIGPYYINHLAQSTQLEDP 132
Cdd:pfam00397    1 LPPGWEERWDPDGRVYYYNHETGETQWEKP 30

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 665394080    707 VLVVSLERANNLLALwtASADNSQVYLRAALLPNSLTSIRTKALGDFQKPVFNDTFAVPITLDKLltKSLQVTVVTM-TG 785
Cdd:smart00239    1 TLTVKIISARNLPPK--DKGGKSDPYVKVSLDGDPKEKKKTKVVKNTLNPVWNETFEFEVPPPEL--AELEIEVYDKdRF 76

                            90       100
                    ....*....|....*....|....*
gi 665394080    786 QKEEIIGTVQISMAEFNPEDSTLKW 810
Cdd:smart00239   77 GRDDFIGQVTIPLSDLLLGGRHEKL 101

Two conserved tryptophans domain; also known as the WWP or rsp5 domain; around 40 amino acids; functions as an interaction module in a diverse set of signalling proteins; binds specific proline-rich sequences but at low affinities compared to other peptide recognition proteins such as antibodies and receptors; WW domains have a single groove formed by a conserved Trp and Tyr which recognizes a pair of residues of the sequence X-Pro; variable loops and neighboring domains confer specificity in this domain; there are five distinct groups based on binding: 1) PPXY motifs 2) the PPLP motif; 3) PGM motifs; 4) PSP or PTP motifs; 5) PR motifs.

                          10        20
                  ....*....|....*....|....*...
gi 665394080  106 GWEESYDPNIGPYYINHLAQSTQLEDPR 133
Cdd:cd00201     3 GWEERWDPDGRVYYYNHNTKETQWEDPR 30

C2 domain found in Human protein Kibra; Kibra is thought to be a regulator of the Salvador (Sav)/Warts (Wts)/Hippo (Hpo) (SWH) signaling network, which limits tissue growth by inhibiting cell proliferation and promoting apoptosis. The core of the pathway consists of a MST and LATS family kinase cascade that ultimately phosphorylates and inactivates the YAP/Yorkie (Yki) transcription coactivator. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are part of the upstream regulation controlling pathway mechanism. Kibra colocalizes and associates with Mer and Ex and is thought to transduce an extracellular signal via the SWH network. The apical scaffold machinery that contains Hpo, Wts, and Ex recruits Yki to the apical membrane facilitating its inhibitory phosphorlyation by Wts. Since Kibra associates with Ex and is apically located it is hypothesized that KIBRA is part of the scaffold, helps in the Hpo/Wts complex, and helps recruit Yki for inactivation that promotes SWH pathway activity. Kibra contains two amino-terminal WW domains, an internal C2-like domain, and a carboxy-terminal glutamic acid-rich stretch. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665394080  693 AQVQIGLKYLKQEGVLVVSLERANNLLALwtASADNSQVYLRAALLP---NSLTSIRTKALGDFQKPVFNDTFAVPITLD 769
Cdd:cd08680     1 AQVQIGLRYDSGDSSLVISVEQLRNLSAL--SIPENSKVYVRVALLPcssSTSCLFRTKALEDQDKPVFNEVFRVPISST 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 665394080  770 KLLTKSLQVTVVTMTG-QKEEIIGTVQISMAEF-NPEDSTLKWYNV 813
Cdd:cd08680    79 KLYQKTLQVDVCSVGPdQQEECLGGAQISLADFeSSEEMSTKWYNL 124

Two conserved tryptophans domain; also known as the WWP or rsp5 domain; around 40 amino acids; functions as an interaction module in a diverse set of signalling proteins; binds specific proline-rich sequences but at low affinities compared to other peptide recognition proteins such as antibodies and receptors; WW domains have a single groove formed by a conserved Trp and Tyr which recognizes a pair of residues of the sequence X-Pro; variable loops and neighboring domains confer specificity in this domain; there are five distinct groups based on binding: 1) PPXY motifs 2) the PPLP motif; 3) PGM motifs; 4) PSP or PTP motifs; 5) PR motifs.

                          10        20        30
                  ....*....|....*....|....*....|.
gi 665394080   57 PDGWDIAKDFDGKTYYIDHINKKTTWLDPRD 87
Cdd:cd00201     1 PPGWEERWDPDGRVYYYNHNTKETQWEDPRE 31

C2 domain second repeat present in Rabphilin and Double C2 domain; Rabphilin is found neurons and in neuroendrocrine cells, while Doc2 is found not only in the brain but in tissues, including mast cells, chromaffin cells, and osteoblasts. Rabphilin and Doc2s share highly homologous tandem C2 domains, although their N-terminal structures are completely different: rabphilin contains an N-terminal Rab-binding domain (RBD),7 whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665394080  694 QVQIGLKYLKQEGVLVVSLERANNLLALwtASADNSQVYLRAALLPNS------LTSIRTKALgdfqKPVFNDTFAVPIT 767
Cdd:cd08384     1 KILVSLMYNTQRRGLIVGIIRCVNLAAM--DANGYSDPFVKLYLKPDAgkkskhKTQVKKKTL----NPEFNEEFFYDIK 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 665394080  768 LDKLLTKSLQVTVVTM-TGQKEEIIGTVQISMaefNPEDSTLK-WYNVL 814
Cdd:cd08384    75 HSDLAKKTLEITVWDKdIGKSNDYIGGLQLGI---NAKGERLRhWLDCL 120

WW domain; The WW domain is a protein module with two highly conserved tryptophans that binds proline-rich peptide motifs in vitro.

                           10        20        30
                   ....*....|....*....|....*....|
gi 665394080    56 LPDGWDIAKDFDGKTYYIDHINKKTTWLDP 85
Cdd:pfam00397    1 LPPGWEERWDPDGRVYYYNHETGETQWEKP 30

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 665394080  694 QVQIGLKYLKQEGVLVVSLERANNLlalwtASADN----SQVYLRAALLPN------SLTSIRTKALgdfqKPVFNDTFA 763
Cdd:cd08521     2 EIEFSLSYNYKTGSLEVHIKECRNL-----AYADEkkkrSNPYVKVYLLPDkskqskRKTSVKKNTT----NPVFNETLK 72

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 665394080  764 VPITLDKLLTKSLQVTV--VTMTGQKeEIIGTVQISMAEFNPEDSTLKWYN 812
Cdd:cd08521    73 YHISKSQLETRTLQLSVwhHDRFGRN-TFLGEVEIPLDSWDLDSQQSEWYP 122

C2 domain first repeat present in Rabphilin and Double C2 domain; Rabphilin is found neurons and in neuroendrocrine cells, while Doc2 is found not only in the brain but in tissues, including mast cells, chromaffin cells, and osteoblasts. Rabphilin and Doc2s share highly homologous tandem C2 domains, although their N-terminal structures are completely different: rabphilin contains an N-terminal Rab-binding domain (RBD),7 whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665394080  692 LAQVQIGLKYLKQEGVLVVSLERANNLLAlwTASADNSQVYLRAALLPNSLTS--IRTKALGDFQKPVFNDTFA-VPITL 768
Cdd:cd04035     1 LGTLEFTLLYDPANSALHCTIIRAKGLKA--MDANGLSDPYVKLNLLPGASKAtkLRTKTVHKTRNPEFNETLTyYGITE 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 665394080  769 DKLLTKSLQVTVVTMTGQKEEIIGTVQISMAEFNPEdsTLKWYNV 813
Cdd:cd04035    79 EDIQRKTLRLLVLDEDRFGNDFLGETRIPLKKLKPN--QTKQFNI 121

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 665394080  694 QVQIGLKYLKQEGVLVVSLERANNLlalwtASADNSQV---YLRAALLPN-SLTSIR-TKALGDFQKPVFNDTFAVP-IT 767
Cdd:cd04031     4 RIQIQLWYDKVTSQLIVTVLQARDL-----PPRDDGSLrnpYVKVYLLPDrSEKSKRrTKTVKKTLNPEWNQTFEYSnVR 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 665394080  768 LDKLLTKSLQVTVVTMTGQKE-EIIGTVQISMAEfNPEDSTLKWYN 812
Cdd:cd04031    79 RETLKERTLEVTVWDYDRDGEnDFLGEVVIDLAD-ALLDDEPHWYP 123

C2A domain first repeat present in Synaptotagmins 1, 5, 6, 9, and 10; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 1, a member of class 1 synaptotagmins, is located in the brain and endocranium and localized to the synaptic vesicles and secretory granules. It functions as a Ca2+ sensor for fast exocytosis as do synaptotagmins 5, 6, and 10. It is distinguished from the other synaptotagmins by having an N-glycosylated N-terminus. Synaptotagmins 5, 6, and 10, members of class 3 synaptotagmins, are located primarily in the brain and localized to the active zone and plasma membrane. They is distinguished from the other synaptotagmins by having disulfide bonds at its N-terminus. Synaptotagmin 6 also regulates the acrosome reaction, a unique Ca2+-regulated exocytosis, in sperm. Synaptotagmin 9, a class 5 synaptotagmins, is located in the brain and localized to the synaptic vesicles. It is thought to be a Ca2+-sensor for dense-core vesicle exocytosis. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665394080  692 LAQVQIGLKYLKQEGVLVVSLERANNLLALwtASADNSQVYLRAALLPNSLTSIRTKAlgdFQK---PVFNDTFAVPITL 768
Cdd:cd08385     2 LGKLQFSLDYDFQSNQLTVGIIQAADLPAM--DMGGTSDPYVKVYLLPDKKKKFETKV---HRKtlnPVFNETFTFKVPY 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 665394080  769 DKLLTKSLQVTVVTMTG-QKEEIIGTVQISMAEFNPEDSTLKWYNVLS 815
Cdd:cd08385    77 SELGNKTLVFSVYDFDRfSKHDLIGEVRVPLLTVDLGHVTEEWRDLES 124

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665394080  694 QVQIGLKYLKQEGVLVVSLERANNLLAL-WTASADNsqvYLRAALLPNSLTSIRTKALGDFQKPVFNDTFAVPITLDKLL 772
Cdd:cd08387     4 ELHFSLEYDKDMGILNVKLIQARNLQPRdFSGTADP---YCKVRLLPDRSNTKQSKIHKKTLNPEFDESFVFEVPPQELP 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 665394080  773 TKSLQVTVVTMTG-QKEEIIGTVQISMAEFN 802
Cdd:cd08387    81 KRTLEVLLYDFDQfSRDECIGVVELPLAEVD 111

Two conserved tryptophans domain; also known as the WWP or rsp5 domain; around 40 amino acids; functions as an interaction module in a diverse set of signalling proteins; binds specific proline-rich sequences but at low affinities compared to other peptide recognition proteins such as antibodies and receptors; WW domains have a single groove formed by a conserved Trp and Tyr which recognizes a pair of residues of the sequence X-Pro; variable loops and neighboring domains confer specificity in this domain; there are five distinct groups based on binding: 1) PPXY motifs 2) the PPLP motif; 3) PGM motifs; 4) PSP or PTP motifs; 5) PR motifs.

                          10        20
                  ....*....|....*....|....*...
gi 665394080  106 GWEESYDPNIGPYYINHLAQSTQLEDPR 133
Cdd:cd00201     3 GWEERWDPDGRVYYYNHNTKETQWEDPR 30

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665394080  695 VQIGLKYLKQEGVLVVSLERANNLlalwtASAD----NSQVYLRAALLPNSL------TSIRTKALgdfqKPVFNDTFAV 764
Cdd:cd08393     4 VQFALDYDPKLRELHVHVIQCQDL-----AAADpkkqRSDPYVKTYLLPDKSnrgkrkTSVKKKTL----NPVFNETLRY 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 665394080  765 PITLDKLLTKSLQVTVVTM-TGQKEEIIGTVQISMAEFNPEDSTLKWYN 812
Cdd:cd08393    75 KVEREELPTRVLNLSVWHRdSLGRNSFLGEVEVDLGSWDWSNTQPTWYP 123