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 705661958  29 GQLKLSVEVQGRVLVLHVMEAKGLMGKEYQTCDSYVKMSIVPDADWKCRQKTKTVPDSKNPVFHEHFLFPVQEEDEQKRL 108
Cdd:cd08685    1 GQLKLSIEGQNRKLTLHVLEAKGLRSTNSGTCNSYVKISLSPDKEVRFRQKTSTVPDSANPLFHETFSFDVNERDYQKRL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 705661958 109 LVTVWNRERNSRQSELIGCMSFGVKSLLtLDKEISGWYYL 148
Cdd:cd08685   81 LVTVWNKLSKSRDSGLLGCMSFGVKSIV-NQKEISGWYYL 119

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 705661958  29 GQLKLSVEVQGRVLVLHVMEAKGLMGKEYQTCDSYVKMSIVPDADWKCRQKTKTVPDSKNPVFHEHFLFPVQEEDEQKRL 108
Cdd:cd08685    1 GQLKLSIEGQNRKLTLHVLEAKGLRSTNSGTCNSYVKISLSPDKEVRFRQKTSTVPDSANPLFHETFSFDVNERDYQKRL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 705661958 109 LVTVWNRERNSRQSELIGCMSFGVKSLLtLDKEISGWYYL 148
Cdd:cd08685   81 LVTVWNKLSKSRDSGLLGCMSFGVKSIV-NQKEISGWYYL 119

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 705661958   41 VLVLHVMEAKGLMGKE-YQTCDSYVKMSIVpdaDWKCRQKTKTVPDSKNPVFHEHFLFPVQEEdEQKRLLVTVWNRERNS 119
Cdd:pfam00168   2 RLTVTVIEAKNLPPKDgNGTSDPYVKVYLL---DGKQKKKTKVVKNTLNPVWNETFTFSVPDP-ENAVLEIEVYDYDRFG 77

                          90       100
                  ....*....|....*....|....*....
gi 705661958  120 RqSELIGCMSFGVKSLLtLDKEISGWYYL 148
Cdd:pfam00168  78 R-DDFIGEVRIPLSELD-SGEGLDGWYPL 104

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 705661958   193 ITIPRGSDGFGFTIC----CDSPVRVQAVDSGGPAEKAGLQQLDTVLQLNQQPVEHWKCVDLAHEIRNCPTEIILLVWR 267
Cdd:smart00228   5 VELEKGGGGLGFSLVggkdEGGGVVVSSVVPGSPAAKAGLRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGKVTLTVLR 83

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 705661958 188 GVSLQITIPRGSDGFGFTIccDSPVRVQAVDSGGPAEKAGLQQLDTVLQLNQQPVEHWKcvDLAHEIRNCP--TEIILLV 265
Cdd:COG0265  181 GVTIQPVTPELAEALGLPE--PEGVLVARVEPGSPAAKAGLRPGDVILAVDGKPVTSAR--DLQRLLASLKpgDTVTLTV 256

                 ..
gi 705661958 266 WR 267
Cdd:COG0265  257 LR 258

periplasmic serine protease, Do/DeqQ family; This family consists of a set proteins various designated DegP, heat shock protein HtrA, and protease DO. The ortholog in Pseudomonas aeruginosa is designated MucD and is found in an operon that controls mucoid phenotype. This family also includes the DegQ (HhoA) paralog in E. coli which can rescue a DegP mutant, but not the smaller DegS paralog, which cannot. Members of this family are located in the periplasm and have separable functions as both protease and chaperone. Members have a trypsin domain and two copies of a PDZ domain. This protein protects bacteria from thermal and other stresses and may be important for the survival of bacterial pathogens.// The chaperone function is dominant at low temperatures, whereas the proteolytic activity is turned on at elevated temperatures. [Protein fate, Protein folding and stabilization, Protein fate, Degradation of proteins, peptides, and glycopeptides]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 705661958  154 GRTKHLKVATQRLKQNRGASPRwGVPGFAGEG-DSGVSLQITIPRGSDGfgfticcdspVRVQAVDSGGPAEKAGLQQLD 232
Cdd:TIGR02037 316 GKEKTITVTLGASPEEQASSSN-PFLGLTVANlSPEIRKELRLKGDVKG----------VVVTKVVSGSPAARAGLQPGD 384

                          90
                  ....*....|.
gi 705661958  233 TVLQLNQQPVE 243
Cdd:TIGR02037 385 VILSVNQQPVS 395

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 705661958  29 GQLKLSVEVQGRVLVLHVMEAKGLMGKEYQTCDSYVKMSIVPDADWKCRQKTKTVPDSKNPVFHEHFLFPVQEEDEQKRL 108
Cdd:cd08685    1 GQLKLSIEGQNRKLTLHVLEAKGLRSTNSGTCNSYVKISLSPDKEVRFRQKTSTVPDSANPLFHETFSFDVNERDYQKRL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 705661958 109 LVTVWNRERNSRQSELIGCMSFGVKSLLtLDKEISGWYYL 148
Cdd:cd08685   81 LVTVWNKLSKSRDSGLLGCMSFGVKSIV-NQKEISGWYYL 119

C2 domain in Protein Kinase C (PKC) alpha and gamma; A single C2 domain is found in PKC alpha and gamma. The PKC family of serine/threonine kinases regulates apoptosis, proliferation, migration, motility, chemo-resistance, and differentiation. There are 3 groups: group 1(alpha, betaI, beta II, gamma) which require phospholipids and calcium, group 2 (delta, epsilon, theta, eta) which do not require calcium for activation, and group 3 (xi, iota/lambda) which are atypical and can be activated in the absence of diacylglycerol and calcium. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have a type-I topology.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 705661958  29 GQLKLSVEVQGRVLVLHVMEAKGL--MGKEYQTcDSYVKMSIVPDADWKCRQKTKTVPDSKNPVFHEHFLFPVQEEDEQK 106
Cdd:cd04026    2 GRIYLKISVKDNKLTVEVREAKNLipMDPNGLS-DPYVKLKLIPDPKNETKQKTKTIKKTLNPVWNETFTFDLKPADKDR 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 705661958 107 RLLVTVWNRERNSRqSELIGCMSFGVKSLltLDKEISGWYYLLGEDLGRTKH 158
Cdd:cd04026   81 RLSIEVWDWDRTTR-NDFMGSLSFGVSEL--IKMPVDGWYKLLNQEEGEYYN 129

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 705661958  42 LVLHVMEAKGLMGKEYQ-TCDSYVKMSIVPdadwKCRQKTKTVPDSKNPVFHEHFLFPVQEEDEQkRLLVTVWNRERNSR 120
Cdd:cd00030    1 LRVTVIEARNLPAKDLNgKSDPYVKVSLGG----KQKFKTKVVKNTLNPVWNETFEFPVLDPESD-TLTVEVWDKDRFSK 75

                         90       100
                 ....*....|....*....|....*...
gi 705661958 121 QsELIGCMSFGVKSLLTLDKEISGWYYL 148
Cdd:cd00030   76 D-DFLGEVEIPLSELLDSGKEGELWLPL 102

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 705661958  28 FGQLKLSVE--VQGRVLVLHVMEAKGLMGK-EYQTCDSYVKMSIVPDADWKCRQKTKTVPDSKNPVFHEHFLFPVQEEDE 104
Cdd:cd04030    2 LGRIQLTIRysSQRQKLIVTVHKCRNLPPCdSSDIPDPYVRLYLLPDKSKSTRRKTSVKKDNLNPVFDETFEFPVSLEEL 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 705661958 105 QKRLL-VTVWN-RERNSRQSELIGCMSFGVkSLLTLDKEISGWYYL 148
Cdd:cd04030   82 KRRTLdVAVKNsKSFLSREKKLLGQVLIDL-SDLDLSKGFTQWYDL 126

C2A domain first repeat present in Synaptotagmins 15 and 17; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. It is thought to be involved in the trafficking and exocytosis of secretory vesicles in non-neuronal tissues and is Ca2+ independent. Human synaptotagmin 15 has 2 alternatively spliced forms that encode proteins with different C-termini. The larger, SYT15a, contains a N-terminal TM region, a putative fatty-acylation site, and 2 tandem C terminal C2 domains. The smaller, SYT15b, lacks the C-terminal portion of the second C2 domain. Unlike most other synaptotagmins it is nearly absent in the brain and rather is found in the heart, lungs, skeletal muscle, and testis. Synaptotagmin 17 is located in the brain, kidney, and prostate and is thought to be a peripheral membrane protein. 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 705661958  29 GQLKLSVE--VQGRVLVLHVMEAKGLMG--KEYQTCDSYVKMSIVPDAdwKCRQKTKTVPDSKNPVFHEHFLFPVQEEDE 104
Cdd:cd08390    1 GRLWFSVQydLEEEQLTVSLIKARNLPPrtKDVAHCDPFVKVCLLPDE--RRSLQSKVKRKTQNPNFDETFVFQVSFKEL 78

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 705661958 105 QKR-LLVTVWNRERNSRQSeLIGCMSFGVKSLLTLDKEI 142
Cdd:cd08390   79 QRRtLRLSVYDVDRFSRHC-IIGHVLFPLKDLDLVKGGV 116

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains 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 705661958 193 ITIPRGS-DGFGFTIC----CDSPVRVQAVDSGGPAEKAG-LQQLDTVLQLNQQPVEHWKCVDLAHEIRNCPTEIILLV 265
Cdd:cd00136    2 VTLEKDPgGGLGFSIRggkdGGGGIFVSRVEPGGPAARDGrLRVGDRILEVNGVSLEGLTHEEAVELLKSAGGEVTLTV 80

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 705661958   193 ITIPRGSDGFGFTIC----CDSPVRVQAVDSGGPAEKAGLQQLDTVLQLNQQPVEHWKCVDLAHEIRNCPTEIILLVWR 267
Cdd:smart00228   5 VELEKGGGGLGFSLVggkdEGGGVVVSSVVPGSPAAKAGLRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGKVTLTVLR 83

PDZ domain of DEP domain-containing mTOR-interacting protein (DEPTOR), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of DEPTOR, and related domains. DEPTOR (also known as DEP domain-containing protein 6, DEP6) is a regulatory protein of mTOR signaling; it is a negative regulator of both the mTORC1 and mTORC2 signaling pathways. DEPTOR's PDZ domain binds to mTOR's FAT domain to suppress mTOR's kinase activity. The DEPTOR PDZ domain also binds lysine-specific demethylase 4A (KDM4A), leucine-rich repeat containing 4 (LRRC4), p38gamma, and major intrinsically disordered Notch2-binding receptor 1 (MINAR1, also known as Ubtor). DEPTOR also interacts with salt-inducible kinase 3 (SIK3). 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 DEPTOR-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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 705661958 193 ITIPRGSDGFGFTICCDSPVRVQAVDSGGPAEKAGLQQLDTVLQLNQQPVEHWKCVDLAHEIRNCPTEIILLV 265
Cdd:cd23067    2 LTIVGDAVGWGFVVRGSKPCHIQAVDPSGPAAAAGMKVCQFIVSVNGLNVLHMDHRTVSNLILTGPRTIVMEV 74

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 705661958  27 TFGQLKLSV--EVQGRVLVLHVMEAKGLMGKEYQTC-DSYVKMSIVPDADWKCRQKTKTVPDSKNPVFHEHFLFP-VQEE 102
Cdd:cd04031    1 ITGRIQIQLwyDKVTSQLIVTVLQARDLPPRDDGSLrNPYVKVYLLPDRSEKSKRRTKTVKKTLNPEWNQTFEYSnVRRE 80

                         90
                 ....*....|....*.
gi 705661958 103 DEQKRLL-VTVWNRER 117
Cdd:cd04031   81 TLKERTLeVTVWDYDR 96

PDZ domain of FERM and PDZ domain-containing protein 1 (FRMPD1), FRMPD3, FRMPD4, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of FRMPD1, FRMPD3, FRMPD4, and related domains. FRMPD1 (also known as FERM domain-containing protein 2, FRMD2), inhibits the malignant phenotype of lung cancer by activating the Hippo pathway via interaction with WWC3; the FRMPD1 PDZ domain binds WWC3. FRMPD3 is a target gene of the neuron-specific transcription factor NPAS4 that is involved in synaptic plasticity. FRMPD4 (also known as PDZ domain-containing protein 10, PDZD10, PDZK10, PSD-95-interacting regulator of spine morphogenesis, and Preso) regulates dendritic spine morphogenesis, and mGluR1/5 signaling; the FRMPD4 PDZ domain binds PAK-interacting exchange factor-beta (betaPix). 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 FRMPD1,3,4-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 705661958 192 QITIPRGSD-GFGFTICCDSPVRVQAVDSGGPAEkAGLQQLDTVLQLNQQPVEhwkcvDLAHE-----IRNCPTEIILLV 265
Cdd:cd06769    1 TVEIQRDAVlGFGFVAGSERPVVVRSVTPGGPSE-GKLLPGDQILKINNEPVE-----DLPRErvidlIRECKDSIVLTV 74

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 705661958  42 LVLHVMEAKGLM-GKEY-QTCDSYVKMSIVPDadwKCRQ---KTKTVPDSKNPVFHEHFLFPVQEED-EQKRLLVTVWNR 115
Cdd:cd08521   16 LEVHIKECRNLAyADEKkKRSNPYVKVYLLPD---KSKQskrKTSVKKNTTNPVFNETLKYHISKSQlETRTLQLSVWHH 92

                 ....*
gi 705661958 116 ERNSR 120
Cdd:cd08521   93 DRFGR 97

PDZ domains of the Na+/H+ exchange regulatory cofactor (NHERF) family (NHERF1-4), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of the Na+/H+ exchange regulatory cofactor (NHERF) family of multi-PDZ-domain-containing scaffolding proteins (NHERF1-4), and related domains. The NHERF family includes NHERF1 (also known as EBP50), NHERF2 (also known as E3KARP; TKA-1; SIP-1), NHERF3 (also known as CAP70; CLAMP; Napi-Cap-1; PDZD1) and NHERF4 (also known as IKEPP; PDZK2; Napi-Cap-2). NHERF1 and NHERF2 have tandem PDZ domains (PDZ1-2); NHERF3 and NHERF4 have four PDZ domains (PDZ1-4). NHERFs are involved in the regulation of multiple receptors or transporters, such as type II sodium-phosphate cotransporter (Npt2a), purinergic P2Y1 receptor P2Y1R, the beta2-adrenergic receptor (beta2-AR), parathyroid hormone receptor type 1 (PTHR), the lysophosphatidic acid receptors (LPARs), sodium-hydrogen exchanger 3 (NHE3), and cystic fibrosis transmembrane conductance regulator (CFTR). NHERF-PDZ1 domain interaction partners include Npt2a, purinergic P2Y1 receptor, beta2-AR, CFTR, PTHR, NH3, G-protein-coupled receptor kinase 6 (GRK6A), platelet-derived growth factor receptor (PDGFR), B1 subunit of the H+ATPase, cholesterol, receptor for activated C-kinase RACK1, aquaporin 9, among others. The NHERF PDZ2 domain interacts with fewer proteins: NHERF1 PDZ2 binds Npt2a, PTHR, beta-catenin, aquaporin 9, and RACK1; NHERF2 PDZ2 binds LPA2, P2Y1R, and NHE3, cGMP-dependent protein kinase type II (cGKII). NHERF4 PDZ1 and PDZ4 bind the epithelial Ca(2+) channels TRPV5 and TRPV6. NHERF2/NHERF3 heterodimerization is mediated by PDZ domains of NHERF2 and the C-terminal PDZ domain recognition motif of NHERF3. NHERF4 regulates several transporters mediating influx of xenobiotics and nutrients in the small intestine. 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 NHERF-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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 705661958 197 RGSDGFGFTICCDSPVR---VQAVDSGGPAEKAGLQQLDTVLQLNQQPVEHWKCVDLAHEIRNCPTEIILLV 265
Cdd:cd06768    7 KGPEGYGFNLHAEKGRPghfIREVDPGSPAERAGLKDGDRLVEVNGENVEGESHEQVVEKIKASGNQVTLLV 78

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 705661958  30 QLKLSVEVQGRVLVLHVMEAKGLMGKEYQT-CDSYVKMSIVPDADWKCRQKTKTVPDSKNPVFHEHFLFPVQEED-EQKR 107
Cdd:cd08384    3 LVSLMYNTQRRGLIVGIIRCVNLAAMDANGySDPFVKLYLKPDAGKKSKHKTQVKKKTLNPEFNEEFFYDIKHSDlAKKT 82

                         90       100
                 ....*....|....*....|....*..
gi 705661958 108 LLVTVWNRERnSRQSELIGCMSFGVKS 134
Cdd:cd08384   83 LEITVWDKDI-GKSNDYIGGLQLGINA 108

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 705661958  42 LVLHVMEAKGLMGKEYQ-TCDSYVKMsivpDADWKcRQKTKTVPDSKNPVFHEHFLFPV-QEEDEQ-KRLLVTVWNRERN 118
Cdd:cd04022    2 LVVEVVDAQDLMPKDGQgSSSAYVEL----DFDGQ-KKRTRTKPKDLNPVWNEKLVFNVsDPSRLSnLVLEVYVYNDRRS 76

                         90       100       110
                 ....*....|....*....|....*....|
gi 705661958 119 SRQSELIGCMSFGVKSLLTLDKEISGWYYL 148
Cdd:cd04022   77 GRRRSFLGRVRISGTSFVPPSEAVVQRYPL 106

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 705661958  30 QLKLSVEVQGRVLVLHVMEAKGLMGKEY-QTCDSYVKMSIVP-DADWKCRQKTKTVPDSKNPVFHEHFLFPV-QEEDEQK 106
Cdd:cd08680    4 QIGLRYDSGDSSLVISVEQLRNLSALSIpENSKVYVRVALLPcSSSTSCLFRTKALEDQDKPVFNEVFRVPIsSTKLYQK 83

                         90       100
                 ....*....|....*....|.
gi 705661958 107 RLLVTVWNReRNSRQSELIGC 127
Cdd:cd08680   84 TLQVDVCSV-GPDQQEECLGG 103

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 705661958  29 GQLKLSVEVQGRVLVLHV--MEAKGLMGKEYQ-TCDSYVKMSIVPDAD--WKCRQKTKTVpdskNPVFHEHFLFPVQEED 103
Cdd:cd08387    3 GELHFSLEYDKDMGILNVklIQARNLQPRDFSgTADPYCKVRLLPDRSntKQSKIHKKTL----NPEFDESFVFEVPPQE 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 705661958 104 EQKRLL-VTVWNRERNSRQsELIGCMSFGVKSlLTLDKEISGW 145
Cdd:cd08387   79 LPKRTLeVLLYDFDQFSRD-ECIGVVELPLAE-VDLSEKLDLW 119

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 705661958  30 QLKLSVEVQGRVLVLHVMEAKGLMGKEYQ-TCDSYVKMSIVPDAdwKCRQKTKTVPDSKNPVFHEHFLF---PVQEEdEQ 105
Cdd:cd08386    6 QFSVSYDFQESTLTLKILKAVELPAKDFSgTSDPFVKIYLLPDK--KHKLETKVKRKNLNPHWNETFLFegfPYEKL-QQ 82

                         90
                 ....*....|....*
gi 705661958 106 KRLLVTVWNRERNSR 120
Cdd:cd08386   83 RVLYLQVLDYDRFSR 97

circularly permuted first PDZ domain (PDZ1) of Escherichia coli periplasmic serine endoprotease DegP and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of Escherichia coli DegP (also known as heat shock protein DegP and Protease Do) and related domains. DegP belongs to the HtrA family of housekeeping proteases. It acts as a protease, degrading transiently denatured and unfolded or misfolded proteins which accumulate in the periplasm following heat shock or other stress conditions, and as a molecular chaperone at low temperatures. DegP has two PDZ domains in addition to the protease domain; its PDZ1 domain is responsible for identifying the distinct substrate sequences that affect degradation (degron) of the substrate sequence, and its PDZ2 domain is responsible for combining with other DegP monomers to form a stable oligomer structure. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains and as well as those with circular permutations and domain swapping of beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. This DegP family PDZ domain 1 is a circularly permuted PDZ domain which places beta-strand A on the C-terminus. Another permutation exists in the PDZ superfamily which places both beta-strands A and B on the C-terminus.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 705661958 217 VDSGGPAEKAGLQQLDTVLQLNQQPVEHWKcvDLAHEIRNCP--TEIILLVWR 267
Cdd:cd10839   32 VLPDSPAAKAGLKAGDVILSLNGKPITSSA--DLRNRVATTKpgTKVELKILR 82

PDZ domain of the microtubule-associated serine-threonine (MAST) protein kinase family; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of MAST family kinases, including MAST1-4. These MAST proteins contain a DUF1908 domain, a serine/threonine kinase domain, a AGC-kinase C-terminal domain, and a PDZ domain; MAST family member MASTL is a shorter protein lacking the PDZ domain. The PDZ domain gives the MAST family the capacity to scaffold its own kinase activity. These kinases are implicated in the inhibition of neurite outgrowth and regeneration in cultured cells. Their binding partners include microtubules, beta2-syntrophin, TNF receptor-associated factor 6 (TRAF6), cAMP-regulated phosphoprotein (ARPP-16), and PTEN. This family also includes Caenorhabditis elegans KIN-4 MAST kinase, a key longevity factor acting through binding PTEN phosphatase, and Drosophila Drop out which regulates dynein-dependent transport during embryonic development. 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 MAST-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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 705661958 193 ITIPRGSDGFGFTIccdSPVRV--------------QAVDSGGPAEKAGLQQLDTVLQLNQQPVE 243
Cdd:cd06705    5 IVIKKGPRGFGFTL---RAIRVyigdsdvytvhhlvTAVEEGSPAYEAGLRPGDLITHVNGEPVQ 66

C2A domain first repeat present in Synaptotagmins 4 and 11; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmins 4 and 11, class 4 synaptotagmins, are located in the brain. Their functions are unknown. They are distinguished from the other synaptotagmins by having and Asp to Ser substitution in their C2A 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 705661958  29 GQL--KLSVEVQGRVLVLHVMEAKGLMGKEYQTC--DSYVKMSIVPDAdwKCRQKTKTVPDSKNPVFHEHF-LFPVQEED 103
Cdd:cd08388    3 GTLffSLRYNSEKKALLVNIIECRDLPAMDEQSGtsDPYVKLQLLPEK--EHKVKTRVLRKTRNPVYDETFtFYGIPYNQ 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 705661958 104 EQKRLL-VTVWNRERNSRQSeLIGCMSFGVKSLLTLDKEIS 143
Cdd:cd08388   81 LQDLSLhFAVLSFDRYSRDD-VIGEVVCPLAGADLLNEGEL 120

PDZ domain 2 of membrane-associated guanylate kinase inverted 1 (MAGI-1), MAGI-2, and MAGI-3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of MAGI1, 2, 3 (MAGI is also known as Membrane-associated guanylate kinase, WW and PDZ domain-containing protein) and related domains. MAGI proteins have been implicated in the control of cell migration and invasion through altering the activity of phosphatase and tensin homolog (PTEN) and modulating Akt signaling. Four MAGI proteins have been identified (MAGI1-3 and MAGIX). MAGI1-3 have 6 PDZ domains and bind to the C-terminus of PTEN via their PDZ2 domain. MAGIX has a single PDZ domain that is related to MAGI1-3 PDZ domain 5. Other binding partners for MAGI1 include JAM4, C-terminal tail of high risk HPV-18 E6, megalin, TRAF6, Kir4.1 (basolateral K+ channel subunit), and cadherin 23; for MAGI2, include DASM1, dendrin, axin, beta- and delta-catenin, neuroligin, hyperpolarization-activated cation channels, beta1-adrenergic receptors, NMDA receptor, and TARPs; and for MAGI3 includes LPA2. 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 MAGI family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as 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 705661958 191 LQITIPRGSDGFGFTIcCDSPV--RV-QAVDsggPAEKAGLQQLDTVLQLNQQPVEHWKCVDLAHEIRNCP--TEIILLV 265
Cdd:cd06732    4 VTVPIVKGPMGFGFTI-ADSPQgqRVkQILD---PQRCRGLQEGDLIVEINGQNVQNLSHAQVVDVLKECPkgSEVTLLV 79

                 ..
gi 705661958 266 WR 267
Cdd:cd06732   80 QR 81

C2 domain second repeat present in Synaptotagmins 14 and 16; Synaptotagmin 14 and 16 are membrane-trafficking proteins in specific tissues outside the brain. Both of these contain C-terminal tandem C2 repeats, but only Synaptotagmin 14 has an N-terminal transmembrane domain and a putative fatty-acylation site. 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 and this is indeed the case here. 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 705661958  32 KLSVEV-QGRVLVLHVMEakglmgkeyQTCDSYVKMSIVpDADWKCRQKTKTV--PDSKNPVFHEHFLFPVQEED-EQKR 107
Cdd:cd08408   16 RLSVEViKGSNFKNLAMN---------KAPDTYVKLTLL-NSDGQEISKSKTSirRGQPDPEFKETFVFQVALFQlSEVT 85

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 705661958 108 LLVTVWNReRNSRQSELIGCMSFGVKSllTLDKEISGW 145
Cdd:cd08408   86 LMFSVYNK-RKMKRKEMIGWFSLGLNS--SGEEEEEHW 120

C2 domain second repeat of Ras GTPase activating proteins (GAPs); RasGAPs suppress Ras function by enhancing the GTPase activity of Ras proteins resulting in the inactive GDP-bound form of Ras. In this way it can control cellular proliferation and differentiation. The proteins here all contain two tandem C2 domains, a Ras-GAP domain, and a pleckstrin homology (PH)-like domain. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have a type-I topology.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 705661958  42 LVLHVMEAKGLMGKEYQTCDSYVKMSIVPDADWKCRqKTKTVPDSKNPVFHEHFLFPV-------------QEEDEQKR- 107
Cdd:cd08675    1 LSVRVLECRDLALKSNGTCDPFARVTLNYSSKTDTK-RTKVKKKTNNPRFDEAFYFELtigfsyekksfkvEEEDLEKSe 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 705661958 108 LLVTVWNrERNSRQSELIGCMSFGVKSlLTLDKEISGWYYLLGEDLGRTK 157
Cdd:cd08675   80 LRVELWH-ASMVSGDDFLGEVRIPLQG-LQQAGSHQAWYFLQPREAPGTR 127

PDZ domain of sorting nexin-27 (SNX27), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SNX27, and related domains. SNX27 is involved in retrograde transport from endosome to plasma membrane. The PDZ domain of SNX27 links cargo identification to retromer-mediated transport. SNX27 binds to the retromer complex (vacuolar protein sorting 26(VPS26)-VPS29-VPS35), via its PDZ domain binding to VPS26. The SNX27 PDZ domain also binds to cargo including the G-protein-coupled receptors (GPCRs): beta2-adrenergic receptor (beta2AR), beta1AR, parathyroid hormone receptor (PTHR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), NMDA receptors, 5-hydroxytryptamine 4a receptors, frizzled receptors, and somatostatin receptor subtype 5 (SSTR5). Additional binding partners of the SNX27 PDZ domain include G protein-gated inwardly rectifying potassium (Kir3) channels, angiotensin-converting enzyme 2 (ACE2), and PTEN (phosphatase and tensin homolog deleted on chromosome 10); PTEN binding to SNX27 prevents SNX27's association with the retromer complex. SNX27 has been reported to be a host factor needed for efficient entry of an engineered SARS-CoV-2 variant, the spike protein of which contains a deletion at the S1/S2 subunit cleavage site; the PDZ domain of SNX27 binds angiotensin-converting enzyme 2 (ACE2), and may be involved in recycling ACE2 to the plasma membrane, thereby promoting viral entry. 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 SNX27-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 705661958 193 ITIPRGSDGFGFTiccdspVR----------------------VQAVDSGGPAEKAGLQQLDTVLQLNQQPVE---HWKC 247
Cdd:cd23070    3 VTIVKSETGFGFN------VRgqvseggqlrsingelyaplqhVSAVLEGGAADKAGVRKGDRILEVNGVNVEgatHKQV 76

                         90
                 ....*....|....*...
gi 705661958 248 VDLaheIRNCPTEIILLV 265
Cdd:cd23070   77 VDL---IKSGGDELTLTV 91

Membrane-associated protease RseP, regulator of RpoE activity [Posttranslational modification, protein turnover, chaperones, Transcription];

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 705661958 210 SPVRVQAVDSGGPAEKAGLQQLDTVLQLNQQPVEHWKcvDLAHEIRNCP-TEIILLVWR 267
Cdd:COG0750  128 TPPVVGEVVPGSPAAKAGLQPGDRIVAINGQPVTSWD--DLVDIIRASPgKPLTLTVER 184

Peptidase family M50;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 705661958  210 SPVRVQAVDSGGPAEKAGLQQLDTVLQLNQQPVEHWkcVDLAHEIRNCPTEIILLVWR 267
Cdd:pfam02163  93 APPVIGGVAPGSPAAKAGLKPGDVILSINGKKITSW--QDLVEALAKSPGKPITLTVE 148