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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372 1534 LGPAQLVGRQTLATPAMGDIQVGMMDKKGQLEVEIIRARGLVVKPGSKTLPAPYVKVYLLDNGVCIAKKKTKVARKTLEP 1613
Cdd:cd04028      1 LGPGQLVGRQVLASPSMGDIQLGLYDKKGQLEVEVIRARGLVQKPGSKVLPAPYVKVYLLEGKKCIAKKKTKIARKTLDP 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958787372 1614 LYQQLLSFEESPQGKVLQIIVWGDYGRMDHKSFMGVAQILLDELELSNMVIGWFKLFPPSSLVDPT 1679
Cdd:cd04028     81 LYQQQLVFDVSPTGKTLQVIVWGDYGRMDKKVFMGVAQILLDDLDLSNLVIGWYKLFPTSSLVDPT 146

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372  711 DRLIGRILLNKRLKDGSvprDSGAMLGLKVVGGKMTESGRLCAFITKVKKGSLADTVGHLRPGDEVLEWNGRLLQGATFE 790
Cdd:cd06714      1 DFLIGRIILQRDPKDGS---VSGNGLGLKVVGGKMTESGRLGAYVTKVKPGSVADTVGHLREGDEVLEWNGISLQGKTFE 77

                           90       100
                   ....*....|....*....|
gi 1958787372  791 EVYNIILESKpePQVELVVS 810
Cdd:cd06714     78 EVQDIISQSK--GEVELVVS 95

BRcat (benign-catalytic) and Rcat (required-for-catalysis) domains, part of the RBR (RING1-BRcat-Rcat) domain; The RBR family of RING-type E3 ligases are characterized by containing an RBR (RING1-BRcat-Rcat) domain, which was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. It is composed of an extended RING domain (RING1) followed by an in-between RING (IBR) domain and the catalytic domain, which is structurally an IBR domain but is commonly designated as RING2. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBRs has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis), where the IBR and RING2 domains have been renamed as BRcat and Rcat domains, respectively. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction. The BRcat domain adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity. RBR family members play roles in protein quality control and can indirectly regulate transcription. Evidence suggests that RBR proteins are often parts of cullin-containing ubiquitin ligase complexes.

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1958787372  174 PTCGI-CHKTkfaDGCGH-NCSYCQTKFCARCGGR 206
Cdd:cd20336      6 PKCKVpIEKN---GGCNHmTCSRCGTEFCWLCGKP 37

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372 1534 LGPAQLVGRQTLATPAMGDIQVGMMDKKGQLEVEIIRARGLVVKPGSKTLPAPYVKVYLLDNGVCIAKKKTKVARKTLEP 1613
Cdd:cd04028      1 LGPGQLVGRQVLASPSMGDIQLGLYDKKGQLEVEVIRARGLVQKPGSKVLPAPYVKVYLLEGKKCIAKKKTKIARKTLDP 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958787372 1614 LYQQLLSFEESPQGKVLQIIVWGDYGRMDHKSFMGVAQILLDELELSNMVIGWFKLFPPSSLVDPT 1679
Cdd:cd04028     81 LYQQQLVFDVSPTGKTLQVIVWGDYGRMDKKVFMGVAQILLDDLDLSNLVIGWYKLFPTSSLVDPT 146

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372  711 DRLIGRILLNKRLKDGSvprDSGAMLGLKVVGGKMTESGRLCAFITKVKKGSLADTVGHLRPGDEVLEWNGRLLQGATFE 790
Cdd:cd06714      1 DFLIGRIILQRDPKDGS---VSGNGLGLKVVGGKMTESGRLGAYVTKVKPGSVADTVGHLREGDEVLEWNGISLQGKTFE 77

                           90       100
                   ....*....|....*....|
gi 1958787372  791 EVYNIILESKpePQVELVVS 810
Cdd:cd06714     78 EVQDIISQSK--GEVELVVS 95

C2 domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372 1562 GQLEVEIIRARGLVVKPGSKTlPAPYVKVYLLDNGVciaKKKTKVARKTLEPLYQQLLSFE-ESPQGKVLQIIVWgDYGR 1640
Cdd:pfam00168    1 GRLTVTVIEAKNLPPKDGNGT-SDPYVKVYLLDGKQ---KKKTKVVKNTLNPVWNETFTFSvPDPENAVLEIEVY-DYDR 75

                           90       100
                   ....*....|....*....|....*....
gi 1958787372 1641 MDHKSFMGVAQILLDELELSNMVIGWFKL 1669
Cdd:pfam00168   76 FGRDDFIGEVRIPLSELDSGEGLDGWYPL 104

Protein kinase C conserved region 2 (CalB); Ca2+-binding motif present in phospholipases, protein kinases C, and synaptotagmins (among others). Some do not appear to contain Ca2+-binding sites. Particular C2s appear to bind phospholipids, inositol polyphosphates, and intracellular proteins. Unusual occurrence in perforin. Synaptotagmin and PLC C2s are permuted in sequence with respect to N- and C-terminal beta strands. SMART detects C2 domains using one or both of two profiles.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372  1563 QLEVEIIRARGLVVKPGSKTlPAPYVKVYLldNGVCIAKKKTKVARKTLEPLYQQLLSFE-ESPQGKVLQIIVWgDYGRM 1641
Cdd:smart00239    1 TLTVKIISARNLPPKDKGGK-SDPYVKVSL--DGDPKEKKKTKVVKNTLNPVWNETFEFEvPPPELAELEIEVY-DKDRF 76

                            90       100
                    ....*....|....*....|....*
gi 1958787372  1642 DHKSFMGVAQILLDELELSNMVIGW 1666
Cdd:smart00239   77 GRDDFIGQVTIPLSDLLLGGRHEKL 101

FYVE-type zinc finger; This FYVE-type zinc finger is found at the N-terminus of effector proteins including rabphilin-3A and regulating synaptic membrane exocytosis protein 2.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1958787372  192 CSYCQTKFCARCGgrvslRSNKEDKVvmWVCNLCRKQQEILTKSGAWFYNS 242
Cdd:pfam02318   74 CLDCRKNVCKKCG-----VYNKPEQG--WLCDPCSEARELKKGSLEWFYKN 117

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372  727 SVPRDSGAMLGLKVVGGkmtesgrlcAFITKVKKGSLADTVGhLRPGDEVLEWNGRLLqgATFEEVYNIILESKPEPQVE 806
Cdd:COG0265    186 PVTPELAEALGLPEPEG---------VLVARVEPGSPAAKAG-LRPGDVILAVDGKPV--TSARDLQRLLASLKPGDTVT 253

                   ....*
gi 1958787372  807 LVVSR 811
Cdd:COG0265    254 LTVLR 258

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372  895 LIVTILGAKDLpSREDGRPRN---PYVKIYFlpdrSDKNKRRTKTVKKTLEPKWNQTFiYSPVHRreFRERmLEITLWDQ 971
Cdd:COG5038    438 VEVKIKSAEGL-KKSDSTINGtvdPYITVTF----SDRVIGKTRVKKNTLNPVWNETF-YILLNS--FTDP-LNLSLYDF 508

                           90       100
                   ....*....|....*....|....*..
gi 1958787372  972 ARVREEesEFLGEILIELetALLDDEP 998
Cdd:COG5038    509 NSFKSD--KVVGSTQLDL--ALLHQNP 531

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372 1534 LGPAQLVGRQTLATPAMGDIQVGMMDKKGQLEVEIIRARGLVVKPGSKTLPAPYVKVYLLDNGVCIAKKKTKVARKTLEP 1613
Cdd:cd04028      1 LGPGQLVGRQVLASPSMGDIQLGLYDKKGQLEVEVIRARGLVQKPGSKVLPAPYVKVYLLEGKKCIAKKKTKIARKTLDP 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958787372 1614 LYQQLLSFEESPQGKVLQIIVWGDYGRMDHKSFMGVAQILLDELELSNMVIGWFKLFPPSSLVDPT 1679
Cdd:cd04028     81 LYQQQLVFDVSPTGKTLQVIVWGDYGRMDKKVFMGVAQILLDDLDLSNLVIGWYKLFPTSSLVDPT 146

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372  711 DRLIGRILLNKRLKDGSvprDSGAMLGLKVVGGKMTESGRLCAFITKVKKGSLADTVGHLRPGDEVLEWNGRLLQGATFE 790
Cdd:cd06714      1 DFLIGRIILQRDPKDGS---VSGNGLGLKVVGGKMTESGRLGAYVTKVKPGSVADTVGHLREGDEVLEWNGISLQGKTFE 77

                           90       100
                   ....*....|....*....|
gi 1958787372  791 EVYNIILESKpePQVELVVS 810
Cdd:cd06714     78 EVQDIISQSK--GEVELVVS 95

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 1958787372  881 RVQIKLWFDKVGHQLIVTILGAKDLPSREDGRPRNPYVKIYFLPDRSDKNKRRTKTVKKTLEPKWNQTFIYsPVHRREFR 960
Cdd:cd04030      4 RIQLTIRYSSQRQKLIVTVHKCRNLPPCDSSDIPDPYVRLYLLPDKSKSTRRKTSVKKDNLNPVFDETFEF-PVSLEELK 82

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1958787372  961 ERMLEITLWDQARVREEESEFLGEILIELETALLDD-EPHWYKLQ 1004
Cdd:cd04030     83 RRTLDVAVKNSKSFLSREKKLLGQVLIDLSDLDLSKgFTQWYDLT 127

C2 domain second repeat present in class II phosphatidylinositol 3-kinases (PI3Ks); There are 3 classes of PI3Ks based on structure, regulation, and specificity. All classes contain a N-terminal C2 domain, a PIK domain, and a kinase catalytic domain. Unlike class I and class III, class II PI3Ks have additionally a PX domain and a C-terminal C2 domain containing a nuclear localization signal both of which bind phospholipids though in a slightly different fashion. PI3Ks (AKA phosphatidylinositol (PtdIns) 3-kinases) regulate cell processes such as cell growth, differentiation, proliferation, and motility. PI3Ks work on phosphorylation of phosphatidylinositol, phosphatidylinositide (4)P (PtdIns (4)P),2 or PtdIns(4,5)P2. Specifically they phosphorylate the D3 hydroxyl group of phosphoinositol lipids on the inositol ring. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372  880 PRVQIKLWFDKVGhqLIVTILGAKDLPSrEDGRPRNPYVKIYFLPDRSDKNKRRTKTVKKTLEPKWNQTFIYSPVHRREF 959
Cdd:cd08381      2 GQVKLSISYKNGT--LFVMVMHAKNLPL-LDGSDPDPYVKTYLLPDPQKTTKRKTKVVRKTRNPTFNEMLVYDGLPVEDL 78

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1958787372  960 RERMLEITLWDQARVReeESEFLGEILIELETALLDDE-PHWYKL 1003
Cdd:cd08381     79 QQRVLQVSVWSHDSLV--ENEFLGGVCIPLKKLDLSQEtEKWYPL 121

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372  894 QLIVTILGAKDLPSREDGRPRNPYVKIYFLPDRSDKNKRRTKTVKKTLEPKWNQTFIYSPVHRREFRERMLEITLWDQAR 973
Cdd:cd04020     28 ELHVWVKEAKNLPALKSGGTSDSFVKCYLLPDKSKKSKQKTPVVKKSVNPVWNHTFVYDGVSPEDLSQACLELTVWDHDK 107

                           90
                   ....*....|
gi 1958787372  974 VreEESEFLG 983
Cdd:cd04020    108 L--SSNDFLG 115

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 1958787372  895 LIVTILGAKDLPSREDGRPRNPYVKIYFLpdrsDKNKRRTKTVKKTLEPKWNQTFIYspvHRREFRERMLEITLWDQARV 974
Cdd:cd00030      1 LRVTVIEARNLPAKDLNGKSDPYVKVSLG----GKQKFKTKVVKNTLNPVWNETFEF---PVLDPESDTLTVEVWDKDRF 73

                           90       100       110
                   ....*....|....*....|....*....|.
gi 1958787372  975 REEesEFLGEILIELETALLDDEPH--WYKL 1003
Cdd:cd00030     74 SKD--DFLGEVEIPLSELLDSGKEGelWLPL 102

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 1958787372  881 RVQIKLWFDKVGHQLIVTILGAKDLPSREDGRPR-NPYVKIYFLPDRSDKNKRRTKTVKKTLEPKWNQTFIYSpVHRREF 959
Cdd:cd08393      3 SVQFALDYDPKLRELHVHVIQCQDLAAADPKKQRsDPYVKTYLLPDKSNRGKRKTSVKKKTLNPVFNETLRYK-VEREEL 81

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 1958787372  960 RERMLEITLWDQARVReeESEFLGEILIELETALLDD-EPHWYKLQ 1004
Cdd:cd08393     82 PTRVLNLSVWHRDSLG--RNSFLGEVEVDLGSWDWSNtQPTWYPLQ 125

C2 domain second repeat present in class II phosphatidylinositol 3-kinases (PI3Ks); There are 3 classes of PI3Ks based on structure, regulation, and specificity. All classes contain a N-terminal C2 domain, a PIK domain, and a kinase catalytic domain. Unlike class I and class III, class II PI3Ks have additionally a PX domain and a C-terminal C2 domain containing a nuclear localization signal both of which bind phospholipids though in a slightly different fashion. PI3Ks (AKA phosphatidylinositol (PtdIns) 3-kinases) regulate cell processes such as cell growth, differentiation, proliferation, and motility. PI3Ks work on phosphorylation of phosphatidylinositol, phosphatidylinositide (4)P (PtdIns (4)P),2 or PtdIns(4,5)P2. Specifically they phosphorylate the D3 hydroxyl group of phosphoinositol lipids on the inositol ring. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372 1551 GDIQVGMMDKKGQLEVEIIRARGLVVKPGSKtlPAPYVKVYLLDNGVCIAKKKTKVARKTLEPLYQQLLSFEESP----Q 1626
Cdd:cd08381      2 GQVKLSISYKNGTLFVMVMHAKNLPLLDGSD--PDPYVKTYLLPDPQKTTKRKTKVVRKTRNPTFNEMLVYDGLPvedlQ 79

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 1958787372 1627 GKVLQIIVWGDyGRMDHKSFMGVAQILLDELELSNMVIGWFKL 1669
Cdd:cd08381     80 QRVLQVSVWSH-DSLVENEFLGGVCIPLKKLDLSQETEKWYPL 121

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 1958787372 1551 GDIQVGMM--DKKGQLEVEIIRARGLVVKPGSKTLPAPYVKVYLLDNGVCIAKKKTKVARKTLEPLYQQLLSF---EESP 1625
Cdd:cd08521      1 GEIEFSLSynYKTGSLEVHIKECRNLAYADEKKKRSNPYVKVYLLPDKSKQSKRKTSVKKNTTNPVFNETLKYhisKSQL 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 1958787372 1626 QGKVLQIIVWgDYGRMDHKSFMGVAQILLDELELSNMVIGWFKL 1669
Cdd:cd08521     81 ETRTLQLSVW-HHDRFGRNTFLGEVEIPLDSWDLDSQQSEWYPL 123

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 1958787372  1563 QLEVEIIRARGLVVKPGSKTlPAPYVKVYLldNGVCIAKKKTKVARKTLEPLYQQLLSFE-ESPQGKVLQIIVWgDYGRM 1641
Cdd:smart00239    1 TLTVKIISARNLPPKDKGGK-SDPYVKVSL--DGDPKEKKKTKVVKNTLNPVWNETFEFEvPPPELAELEIEVY-DKDRF 76

                            90       100
                    ....*....|....*....|....*
gi 1958787372  1642 DHKSFMGVAQILLDELELSNMVIGW 1666
Cdd:smart00239   77 GRDDFIGQVTIPLSDLLLGGRHEKL 101

C2A domain first repeat present in Synaptotagmin 7; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 7, a member of class 2 synaptotagmins, is located in presynaptic plasma membranes in neurons, dense-core vesicles in endocrine cells, and lysosomes in fibroblasts. It has been shown to play a role in regulation of Ca2+-dependent lysosomal exocytosis in fibroblasts and may also function as a vesicular Ca2+-sensor. It is distinguished from the other synaptotagmins by having over 12 splice forms. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372  878 FVPRVQIKLWFDKVGHQLIVTILGAKDLPSREDGRPRNPYVKIYFLPDRsdKNKRRTKTVKKTLEPKWNQTFIYSPVHRR 957
Cdd:cd08386      1 NLGRIQFSVSYDFQESTLTLKILKAVELPAKDFSGTSDPFVKIYLLPDK--KHKLETKVKRKNLNPHWNETFLFEGFPYE 78

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1958787372  958 EFRERMLEITLWDQARVREEESefLGEILIELETALLDDEPHWYK 1002
Cdd:cd08386     79 KLQQRVLYLQVLDYDRFSRNDP--IGEVSLPLNKVDLTEEQTFWK 121

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 1958787372  881 RVQIKLWFDKVGHQLIVTILGAKDLPSREDGRPRNPYVKIYFLPDRsdKNKRRTKTVKKTLEPKWNQTFIYsPVHRREFR 960
Cdd:cd08385      4 KLQFSLDYDFQSNQLTVGIIQAADLPAMDMGGTSDPYVKVYLLPDK--KKKFETKVHRKTLNPVFNETFTF-KVPYSELG 80

                           90
                   ....*....|
gi 1958787372  961 ERMLEITLWD 970
Cdd:cd08385     81 NKTLVFSVYD 90

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 1958787372 1551 GDIQVGMM--DKKGQLEVEIIRARGLVVKPGSKTLPAPYVKVYLLDNGVCIAKKKTKVARKTLEPLYQQLLSFE---ESP 1625
Cdd:cd08393      2 GSVQFALDydPKLRELHVHVIQCQDLAAADPKKQRSDPYVKTYLLPDKSNRGKRKTSVKKKTLNPVFNETLRYKverEEL 81

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 1958787372 1626 QGKVLQIIVWgDYGRMDHKSFMGVAQILLDELELSNMVIGWFKL 1669
Cdd:cd08393     82 PTRVLNLSVW-HRDSLGRNSFLGEVEVDLGSWDWSNTQPTWYPL 124

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372   722 RLKDGSVPRDSGaMLGLKVVGGKMTESGrlcAFITKVKKGSLADTVGhLRPGDEVLEWNGRLLQGATFEEVYNIILESKP 801
Cdd:smart00228    1 EPRLVELEKGGG-GLGFSLVGGKDEGGG---VVVSSVVPGSPAAKAG-LRVGDVILEVNGTSVEGLTHLEAVDLLKKAGG 75

                            90
                    ....*....|.
gi 1958787372   802 EpqVELVVSRP 812
Cdd:smart00228   76 K--VTLTVLRG 84

C2 domain of the Regulator Of G-Protein Signaling (RGS) family; This CD contains members of the regulator of G-protein signaling (RGS) family. RGS is a GTPase activating protein which inhibits G-protein mediated signal transduction. The protein is largely cytosolic, but G-protein activation leads to translocation of this protein to the plasma membrane. A nuclear form of this protein has also been described, but its sequence has not been identified. There are multiple alternatively spliced transcript variants in this family with some members having additional domains (ex. PDZ and RGS) downstream of the 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 1958787372  883 QIKLWFDKVGHQLIVTILGAKDLPSREDGrPRNPYVKIYFLPDRSDKNKRRTKTVKKTLEPKWNQTFIYsPVHRREFRER 962
Cdd:cd08685      2 QLKLSIEGQNRKLTLHVLEAKGLRSTNSG-TCNSYVKISLSPDKEVRFRQKTSTVPDSANPLFHETFSF-DVNERDYQKR 79

                           90       100
                   ....*....|....*....|.
gi 1958787372  963 MLeITLWDQARvREEESEFLG 983
Cdd:cd08685     80 LL-VTVWNKLS-KSRDSGLLG 98

C2 domain first repeat present in Synaptotagmin-like proteins 4 and 5; All Slp members basically share an N-terminal Slp homology domain (SHD) and C-terminal tandem C2 domains (named the C2A domain and the C2B domain) with the SHD and C2 domains being separated by a linker sequence of various length. SHD of Slp (except for the Slp4-SHD) function as a specific Rab27A/B-binding domain. In addition to Slp, rabphilin, Noc2, and Munc13-4 also function as Rab27-binding proteins. It has been demonstrated that Slp4/granuphilin promotes dense-core vesicle exocytosis. The C2A domain of Slp4 is Ca2+ dependent. Slp5 mRNA has been shown to be restricted to human placenta and liver suggesting a role in Rab27A-dependent membrane trafficking in specific tissues. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958787372 1560 KKGQLEVEIIRARGLVVKPGSKTLPAPYVKVYLLDNGVCIAKKKTKVARKTLEPLYQQLLSFEESP---QGKVLQIIVWg 1636
Cdd:cd04029     13 KTQSLNVHVKECRNLAYGDEAKKRSNPYVKTYLLPDKSRQSKRKTSIKRNTTNPVYNETLKYSISHsqlETRTLQLSVW- 91

                           90       100       110
                   ....*....|....*....|....*....|...
gi 1958787372 1637 DYGRMDHKSFMGVAQILLDELELSNMVIGWFKL 1669
Cdd:cd04029     92 HYDRFGRNTFLGEVEIPLDSWNFDSQHEECLPL 124

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 1958787372  880 PRVQIKLWFDKVGHQLIVTILGAKDLPSREDGRPRNPYVKIYFLPDRSDKNKRRTKTVKKTLEPKWNQTFIYsPVHRREF 959
Cdd:cd00276      1 GELLLSLSYLPTAERLTVVVLKARNLPPSDGKGLSDPYVKVSLLQGGKKLKKKKTSVKKGTLNPVFNEAFSF-DVPAEQL 79

                           90       100
                   ....*....|....*....|....*...
gi 1958787372  960 RERMLEITLWDQARVReeESEFLGEILI 987
Cdd:cd00276     80 EEVSLVITVVDKDSVG--RNEVIGQVVL 105

PDZ domain 2 of PDZ domain containing 2 (PDZD2), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of PDZD2, also known as KIAA0300, PIN-1, activated in prostate cancer (AIPC) and PDZ domain-containing protein 3 (PDZK3). PDZD2 has seven PDZ domains, and is expressed at exceptionally high levels in the pancreas and certain cancer tissues such as prostate cancer. It promotes the proliferation of insulinoma cells and is upregulated during prostate tumorigenesis. In osteosarcoma (OS), the microRNA miR-363 acts as a tumor suppressor by inhibiting PDZD2. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This PDZD2-like family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1958787372  736 LGLKVVGGKMTESGRLCAFITKVKKGSLADTVGHLRPGDEVLEWNGRLLQGATFEEVYNiILESKPEPqVELVVSRP 812
Cdd:cd06758     14 LGIQITGGKGSKRGDIGIFVAGVEEGGSADRDGRLKKGDELLMINGQSLIGLSHQEAVA-ILRSSASP-VQLVIASK 88