NCBI Conserved Domain Search

Ras-GTPase Activating Domain of RASA4; Ras GTPase activating-like 4 protein (RASAL4), also known as Ca2+ -promoted Ras inactivator (CAPRI), is a member of the GAP1 family. Members of the GAP1 family are characterized by a conserved domain structure comprising N-terminal tandem C2 domains, a highly conserved central RasGAP domain, and a C-terminal pleckstrin-homology domain that is associated with a Bruton's tyrosine kinase motif. RASAL4, like RASAL, is a cytosolic protein that undergoes a rapid translocation to the plasma membrane in response to a receptor-mediated elevation in the concentration of intracellular free Ca2+ ([Ca2+]i). However, unlike RASAL, RASAL4 does not sense oscillations in [Ca2+]i.

Pssm-ID: 213343 [Multi-domain] Cd Length: 287 Bit Score: 418.51 E-value: 6.00e-142

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 264 PSVCYQPLVQLLCQEVKLGTQ-GPGRLIPVIEETTSAECRQEVATTLLKLFLGQGLAKDFLDLLFQLELGRTSEANTLFR 342
Cdd:cd05395   1 PSSHYQPLVQLLCQEVKLGHQaGPVQLISLIDETTTAECRQEVATNLVKLFLGQGLAKEFLDLLFQLELDKTTEPNTLFR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 343 SNSLASKSMESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVEVKDVGCSGLHRPQTEAEVLEQSAQTLRAHLVAL 422
Cdd:cd05395  81 SNSLASKSMESFLKVAGMQYLHSVLGPTINRVFEEKKYVELDPSKVEIKDVGCSGLHRIQTESEVIEQSAQLLQSYLGEL 160

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 423 LSAICRSVRTCPAIIRATFRQLFRRVRERFPNAQHQ-------------------------------------------- 458
Cdd:cd05395 161 LSAISKSVKYCPAVIRATFRQLFKRVQERFPENQHQnvkfiavtsflclrffspaimspklfhlrekhadartsrtllll 240

                       250       260       270       280
                ....*....|....*....|....*....|....*....|....*..
gi 84993718 459 --AVQNIGNMDTPVSRAKESWMEPLQPTVRQGVAQLKDFIMKLVDIE 503
Cdd:cd05395 241 akAVQNVGNMDTLASRAKEAWMAPLQPAIQQGVAQLKDFITKLVDIE 287

Ras-GTPase Activating Domain of RASAL1 and similar proteins; Ras GTPase activating-like protein (RASAL) or RASAL1 is a member of the GAP1 family, and a Ca2+ sensor responding in-phase to repetitive Ca2+ signals by associating with the plasma membrane and deactivating Ras. It contains a conserved domain structure comprising N-terminal tandem C2 domains, a highly conserved central RasGAP domain, and a C-terminal pleckstrin-homology domain that is associated with a Bruton's tyrosine kinase motif. RASAL, like Ca2+ -promoted Ras inactivator (CAPRI, or RASAL4), is a cytosolic protein that undergoes a rapid translocation to the plasma membrane in response to receptor-mediated elevation in the concentration of intracellular free Ca2+, a translocation that activates its ability to function as a RasGAP. However, unlike RASAL4, RASAL undergoes an oscillatory translocation to the plasma membrane that occurs in synchrony with repetitive Ca2+ spikes.

Pssm-ID: 213337 Cd Length: 287 Bit Score: 267.06 E-value: 1.57e-83

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 264 PSVCYQPLVQLLCQEVKL-GTQGPGRLIPVIEETTSAECRQEVATTLLKLFLGQGLAKDFLDLLFQLELGRTSEANTLFR 342
Cdd:cd05135   1 PSQYYQPLIDLLVESVQSpAEAEDSTPLAMLEEVTTGESRQDVATKLVKIFLGQGLVVPFLDYLNTREVGRTTDPNTLFR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 343 SNSLASKSMESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVEVKDVGCSGLHRPQTEAEVLEQSAQTLRAHLVAL 422
Cdd:cd05135  81 SNSLASKSMEQFMKVVGMPYLHEVLKPVINRIFEEKKYVELDPCKIDLNRTRRISFKGSLSEAQVRESSLELLQGYLGSI 160

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 423 LSAICRSVRTCPAIIRATFRQLFRRVRERFPNAQHQ-------------------------------------------- 458
Cdd:cd05135 161 IDAIVGSVDQCPPVMRVAFKQLHKRVEERFPEAEHQdvkylaisgflflrffapailtpklfqlreqhadprtsrtllll 240

                       250       260       270       280
                ....*....|....*....|....*....|....*....|....*..
gi 84993718 459 --AVQNIGNMDTPVSRAKESWMEPLQPTVRQGVAQLKDFIMKLVDIE 503
Cdd:cd05135 241 akAVQSIGNLGLQLGQGKEQWMAPLHPFILQSVARVKDFLDRLIDID 287

C2 domain first repeat present in RasA1 and RasA4; Rasal1 and RasA4 are both members of GAP1 (GTPase activating protein 1). Rasal1 responds to repetitive Ca2+ signals by associating with the plasma membrane and deactivating Ras. RasA4 suppresses 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. Both of these proteins contains two C2 domains, a Ras-GAP domain, a plextrin homology (PH)-like domain, and a Bruton's Tyrosine Kinase (BTK) zinc binding 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. This cd contains the first C2 repeat, C2A, and has a type-I topology.

Pssm-ID: 176018 [Multi-domain] Cd Length: 121 Bit Score: 247.04 E-value: 2.46e-78

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   6 SLSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDALSRDDVIG 85
Cdd:cd04054   1 SLYIRIVEGKNLPAKDITGSSDPYCIVKVDNEVIIRTATVWKTLNPFWGEEYTVHLPPGFHTVSFYVLDEDTLSRDDVIG 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 84993718  86 KVCLTRDALASHPKGFSGWTHLVEVDPNEEVQGEIHLRLEV 126
Cdd:cd04054  81 KVSLTREVISAHPRGIDGWMNLTEVDPDEEVQGEIHLELSV 121

Ca2+ promoted Ras inactivator pleckstrin homology (PH) domain; CAPRI (also called RASA4/RAS p21 protein activator (GTPase activating protein) 4/GAPL/FLJ59070/KIAA0538/MGC131890) is a member of the GAP1 family of GTPase-activating proteins. CAPRI contains two fully conserved C2 domains, a PH domain, a RasGAP domain, and a BTK domain. Its catalytic GAP domain has dual RasGAP and RapGAP activities, while its C2 domains bind phospholipids in the presence of Ca2+. Both CAPRI and RASAL are calcium-activated RasGAPs that inactivate Ras at the plasma membrane. Thereby enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS and allowing control of cellular proliferation and differentiation. CAPRI and RASAL differ in that CAPRI is an amplitude sensor while RASAL senses calcium oscillations. This difference between them resides not in their C2 domains, but in their PH domains leading to speculation that this might reflect an association with either phosphoinositides and/or proteins. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 241523 Cd Length: 140 Bit Score: 242.08 E-value: 3.12e-76

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 495 FIMKLVDIEEKEELDLQRALNSQAPPVKEGPLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIR 574
Cdd:cd13372   1 FITKLVDIEEEDELDLTRMLLLQAPMVKEGFLFIHRTKGKGPLMASSFKKLYFTLTKDALSFAKTPHSKKSSSISLAKIR 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 575 AAEKVEEKSFGSSHIMQVIYADDVGRAQTVYLQCKCVNELNQWLSALRKASTNNRGLLRS 634
Cdd:cd13372  81 AAEKVEEKCFGSSNVMQIIYTDDAGQQETLYLQCKSVNELNQWLSALRKVCSNNTNLLSS 140

GTPase-activator protein for Ras-like GTPases; All alpha-helical domain that accelerates the GTPase activity of Ras, thereby "switching" it into an "off" position. Improved domain limits from structure.

Pssm-ID: 214617 Cd Length: 344 Bit Score: 246.45 E-value: 6.18e-75

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718    245 KGNLGSLQLEVRLRDETVLPSVCYQPLVQLLCQEVKLgtqgpgRLIPVIEETTSAECRQEVATTLLKLFLGQGLAKDFLD 324
Cdd:smart00323   3 QGDLGSLRLKTVYTTDFILPSEYYEELLELLLFSLDL------SLASALSEVCSGLDKDELATKLVRLFLRRGRGHPFLR 76

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718    325 LLFQLELGRTSEANTLFRSNSLASKSMESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVevkdvgcsglhrpqtE 404
Cdd:smart00323  77 ALIDPEVERTDDPNTIFRGNSLATKSMEVYMKLVGNQYLHTTLKPVLKKIVESKKSCEVDPAKL---------------E 141

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718    405 AEVLEQSAQTLRAHLVALLSAICRSVRTCPAIIRATFRQLFRRVRERFPNAQHQ-------------------------- 458
Cdd:smart00323 142 GEDLETNLENLLQYVERLFDAIINSSDRLPYGLRDICKQLRQAAEKRFPDADVIykavssfvflrffcpaivspklfnlv 221

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718    459 -----------------AVQNIGNMDTpvSRAKESWMEPLQPTVRQGVAQLKDFIMKL-------VDIEEKEELDLQRAL 514
Cdd:smart00323 222 dehpdpttrrtltliakVLQNLANLSE--FGSKEPWMEPLNDFLLSHKDRVKDFLDELssvpeilVDKVSDSTTISGREL 299

                          330       340       350       360
                   ....*....|....*....|....*....|....*....|....*
gi 84993718    515 NSQAPPVKEGPLFIHRTKG-KGPLASSSFKKLYFSLTTEALSFAK 558
Cdd:smart00323 300 SLLHSLLLENGDALKRELNnEDPLGKLLFKLRYFGLTTHELTYGK 344

C2 domain second repeat present in RasA1 and RasA4; RasA1 and RasA4 are GAP1s (GTPase activating protein 1s ), Ras-specific GAP members, which suppresses 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. Both proteins contain two C2 domains, a Ras-GAP domain, a plextrin homology (PH)-like domain, and a Bruton's Tyrosine Kinase (BTK) zinc binding 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. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 175991 [Multi-domain] Cd Length: 123 Bit Score: 225.44 E-value: 3.78e-70

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 134 RLRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRNDFLG 213
Cdd:cd04025   1 RLRCHVLEARDLAPKDRNGTSDPFVRVFYNGQTLETSVVKKSCYPRWNEVFEFELMEGADSPLSVEVWDWDLVSKNDFLG 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 84993718 214 KVAVNVQRLCSAQQEEGWFRLQPDQSKSRQGKGNLGSLQLEVR 256
Cdd:cd04025  81 KVVFSIQTLQQAKQEEGWFRLLPDPRAEEESGGNLGSLRLKVR 123

Ras-GTPase Activating Domain of GAP1 and similar proteins; The GAP1 family of Ras GTPase-activating proteins includes GAP1(m) (or RASA2), GAP1_IP4BP (or RASA3), Ca2+ -promoted Ras inactivator (CAPRI, or RASAL4), and Ras GTPase activating-like proteins (RASAL) or RASAL1. The members are characterized by a conserved domain structure comprising N-terminal tandem C2 domains, a highly conserved central RasGAP domain, and a C-terminal pleckstrin homology domain that is associated with a Bruton's tyrosine kinase motif. While this domain structure is conserved, a small change in the function of each individual domain and the interaction between domains has a marked effect on the regulation of each protein.

Pssm-ID: 213330 Cd Length: 269 Bit Score: 209.80 E-value: 2.67e-62

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 267 CYQPLVQLLCQEVKLGtQGPGRLIPVIEETTSAeCRQEVATTLLKLFLGQGLAKDFLDLLFQLELGRTSEANTLFRSNSL 346
Cdd:cd05128   2 YYEPLLNLLLESLDVP-PFTASAVYLLEELVKV-DKDDVARPLVRIFLHHGQIVPLLRALASREISKTQDPNTLFRGNSL 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 347 ASKSMESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVEVKDvgcsglhrpqteaeVLEQSAQTLRAHLVALLSAI 426
Cdd:cd05128  80 ASKCMDEFMKLVGMQYLHETLKPVIDEIFSEKKSCEIDPSKLKDGE--------------VLETNLANLRGYVERVFKAI 145

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 427 CRSVRTCPAIIRATFRQLFRRVRERFPNAQH--------------------------------------------QAVQN 462
Cdd:cd05128 146 TSSARRCPTLMCEIFSDLRESAAQRFPDNEDvpytavsgfiflrffapailnpklfglreehpdpqtartltlisKTIQT 225

                       250       260       270       280
                ....*....|....*....|....*....|....*....|....
gi 84993718 463 IGNMDTPVS--RAKESWMEPLQ--PTVRQGVAQLKDFIMKLVDI 502
Cdd:cd05128 226 LGNLGSSSSglGVKEAYMSPLYerFTDEQHVDAVKKFLDRISSV 269

C2 domain (first 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 either a single C2 domain or 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.

Pssm-ID: 176029 [Multi-domain] Cd Length: 117 Bit Score: 158.58 E-value: 1.21e-45

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   6 SLSIRIVEGKNLPAKditGSSDPYCIVKVDNEPIIRTATVWKtLCPFWGEDYQVHLPP---TFHTVAFYVMDEDALSRDD 82
Cdd:cd08383   1 SLRLRILEAKNLPSK---GTRDPYCTVSLDQVEVARTKTVEK-LNPFWGEEFVFDDPPpdvTFFTLSFYNKDKRSKDRDI 76

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 84993718  83 VIGKVCLTRDALashPKGFSGWTHLVEVDPNEEVQGEIHLRLEV 126
Cdd:cd08383  77 VIGKVALSKLDL---GQGKDEWFPLTPVDPDSEVQGSVRLRARY 117

RAS p21 protein activator (GTPase activating protein) family pleckstrin homology (PH) domain; RASAL1, GAP1(m), GAP1(IP4BP), and CAPRI are all members of the GAP1 family of GTPase-activating proteins. They contain N-terminal SH2-SH3-SH2 domains, followed by two C2 domains, a PH domain, a RasGAP domain, and a BTK domain. With the notable exception of GAP1(m), they all possess an arginine finger-dependent GAP activity on the Ras-related protein Rap1. They act as a suppressor of RAS enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, allowing control of cellular proliferation and differentiation. PH domains share little sequence conservation, but all have a common fold, which is electrostatically polarized. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 269950 Cd Length: 107 Bit Score: 149.36 E-value: 1.87e-42

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 522 KEGPLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIRAAEKVEEKSFGSSHIMQVIYADdvgra 601
Cdd:cd01244   1 KEGYLIKRAQGRKKKFGRKNFKKRYFRLTNEALSYSKSKGKQPLCSIPLEDILAVERVEEESFKMKNMFQIVQPD----- 75

                        90       100       110
                ....*....|....*....|....*....|.
gi 84993718 602 QTVYLQCKCVNELNQWLSALRKASTNNRGLL 632
Cdd:cd01244  76 RTLYLQAKNVVELNEWLSALRKVCLCNPNRL 106

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.

Pssm-ID: 176057 [Multi-domain] Cd Length: 137 Bit Score: 150.60 E-value: 2.13e-42

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKdRNGASDPFVRVHYNG----RTQETSVVKKSCYPRWNETFDFELEKGAS---------------EA 195
Cdd:cd08675   1 LSVRVLECRDLALK-SNGTCDPFARVTLNYssktDTKRTKVKKKTNNPRFDEAFYFELTIGFSyekksfkveeedlekSE 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 84993718 196 LLVEAWDWDLVSRNDFLGKVAVNVQRLCSAQQEEGWFRLQPDQSKSRQG--KGNLGSL 251
Cdd:cd08675  80 LRVELWHASMVSGDDFLGEVRIPLQGLQQAGSHQAWYFLQPREAPGTRSsnDGSLGSL 137

Ras-GTPase-activating-like protein pleckstrin homology (PH) domain; RASAL1 is a member of the GAP1 family of GTPase-activating proteins, along with GAP1(m), GAP1(IP4BP) and CAPRI. RASAL1 contains two C2 domains, a PH domain, a RasGAP domain, and a BTK domain. RASAL1 contains two fully conserved C2 domains, a PH domain, a RasGAP domain, and a BTK domain. Its catalytic GAP domain has dual RasGAP and RapGAP activities, while its C2 domains bind phospholipids in the presence of Ca2+. Both CAPRI and RASAL1 are calcium-activated RasGAPs that inactivate Ras at the plasma membrane. Thereby enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS and allowing control of cellular proliferation and differentiation. CAPRI and RASAL1 differ in that CAPRI is an amplitude sensor while RASAL1 senses calcium oscillations. This difference between them resides not in their C2 domains, but in their PH domains leading to speculation that this might reflect an association with either phosphoinositides and/or proteins. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270175 Cd Length: 138 Bit Score: 136.53 E-value: 2.27e-37

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 511 QRALNSQAPPVKEGPLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIRAAEKVEEKSFGSSHIM 590
Cdd:cd13369   6 PRALFPPSVTVKEGYLHKRKAEGVGLVTRFTFKKRYFWLSSETLSYSKSPDWQVRSSIPVQRICAVERVDENAFQQPNVM 85

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 84993718 591 QVIYADDVGRAQTVYLQCKCVNELNQWLSALRKASTNNRGLLRSYHPGIFRG 642
Cdd:cd13369  86 QVVTQDGEGQVHTTYIQCKNVNELNQWLSALRKVSLSNERMLPACHPGAFRS 137

Ras GTPase Activating Domain; RasGAP functions as an enhancer of the hydrolysis of GTP that is bound to Ras-GTPases. Proteins having a RasGAP domain include p120GAP, IQGAP, Rab5-activating protein 6, and Neurofibromin, among others. Although the Rho (Ras homolog) GTPases are most closely related to members of the Ras family, RhoGAP and RasGAP exhibit no similarity at their amino acid sequence level. RasGTPases function as molecular switches in a large number of signaling pathways. They are in the on state when bound to GTP, and in the off state when bound to GDP. The RasGAP domain speeds up the hydrolysis of GTP in Ras-like proteins acting as a negative regulator.

Pssm-ID: 213328 Cd Length: 256 Bit Score: 132.23 E-value: 1.76e-34

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 283 TQGPGRLIPVIEETTSAECRQEVATTLLKLFLGQGLAKDFLDLLFQLELGRTSEANTLFRSNSLASKSMESFLKVAGMRY 362
Cdd:cd04519  11 TESPLALLRELSQVLPVKDKEEVATALLRIFESRGLALEFLRYLVRSEVKNTKNPNTLFRGNSLATKLLDQYMKLVGQEY 90

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 363 LHGILGPIIDRVFEEKKYVELDPSKvevkdvgcsglhrpqTEAEVLEQSAQTLRAHLVALLSAICRSVRTCPAIIRATFR 442
Cdd:cd04519  91 LKETLSPLIREILESKESCEIDTKL---------------PVGEDLEENLENLLELVNKLVDRILSSLDRLPPELRYVFK 155

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 443 QLFRRVRERFPNAQHQAVQNIGN----------MDTP--------------------VSR------------AKESWMEP 480
Cdd:cd04519 156 ILREFLAERFPEEPDEAYQAVSGflflrficpaIVSPelfglvpdepseqarrnltlISKvlqslangvefgDKEPFMKP 235

                       250       260
                ....*....|....*....|.
gi 84993718 481 LQPTVRQGVAQLKDFIMKLVD 501
Cdd:cd04519 236 LNDFIKSNKPKLKQFLDELSS 256

C2 domain first repeat present in RasA2 and RasA3; RasA2 and RasA3 are GAP1s (GTPase activating protein 1s ), Ras-specific GAP members, which suppresses 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. RasA2 and RasA3 are both inositol 1,3,4,5-tetrakisphosphate-binding proteins and contain an N-terminal C2 domain, a Ras-GAP domain, a pleckstrin-homology (PH) domain which localizes it to the plasma membrane, and Bruton's Tyrosine Kinase (BTK) a zinc binding 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. This cd contains the first C2 repeat, C2A, and has a type-I topology.

Pssm-ID: 176046 [Multi-domain] Cd Length: 121 Bit Score: 120.23 E-value: 5.46e-32

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   6 SLSIRIVEGKNLPAKDIT-GSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDALSRDDVI 84
Cdd:cd08401   1 SLKIKIGEAKNLPPRSGPnKMRDCYCTVNLDQEEVFRTKTVEKSLCPFFGEDFYFEIPRTFRHLSFYIYDRDVLRRDSVI 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 84993718  85 GKVCLTRDALASHpKGFSGWTHLVEVDPNEEVQGEIHLRL 124
Cdd:cd08401  81 GKVAIKKEDLHKY-YGKDTWFPLQPVDADSEVQGKVHLEL 119

C2 domain;

Pssm-ID: 425499 [Multi-domain] Cd Length: 104 Bit Score: 115.49 E-value: 1.50e-30

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   134 RLRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQ--ETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRNDF 211
Cdd:pfam00168   2 RLTVTVIEAKNLPPKDGNGTSDPYVKVYLLDGKQkkKTKVVKNTLNPVWNETFTFSVPDPENAVLEIEVYDYDRFGRDDF 81

                          90       100
                  ....*....|....*....|...
gi 84993718   212 LGKVAVNVQRLCSAQQEEGWFRL 234
Cdd:pfam00168  82 IGEVRIPLSELDSGEGLDGWYPL 104

GTPase-activator protein for Ras-like GTPase; All alpha-helical domain that accelerates the GTPase activity of Ras, thereby "switching" it into an "off" position.

Pssm-ID: 459871 Cd Length: 207 Bit Score: 115.46 E-value: 3.07e-29

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   322 FLDLLFQLELGRTSEANTLFRSNSLASKSMESFLKVA-GMRYLHGILGPIIDRVFE-EKKYVELDPSKVEVK-------- 391
Cdd:pfam00616   1 LISELIEEEIESSDNPNDLLRGNSLVSKLLETYNRRPrGQEYLKKVLGPLVRKIIEdEDLDLESDPRKIYESlinqeelk 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   392 --------DVGCSGLHRPQTEAEVLEQSAQTLRAHLVALLSAICRSVRTCPAIIRATFRQLFRRVRERFPNAQHQAVQN- 462
Cdd:pfam00616  81 tgrsdlprDVSPEEAIEDPEVRQIFEDNLQKLRELADEFLDAIYSSLNQLPYGIRYICKQLYELLEEKFPDASEEEILNa 160


                  ...
gi 84993718   463 IGN 465
Cdd:pfam00616 161 IGG 163

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.

Pssm-ID: 175973 [Multi-domain] Cd Length: 102 Bit Score: 109.85 E-value: 1.49e-28

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNGASDPFVRVHYNG-RTQETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRNDFLG 213
Cdd:cd00030   1 LRVTVIEARNLPAKDLNGKSDPYVKVSLGGkQKFKTKVVKNTLNPVWNETFEFPVLDPESDTLTVEVWDKDRFSKDDFLG 80

                        90       100
                ....*....|....*....|..
gi 84993718 214 KVAVNVQRLCSAQQE-EGWFRL 234
Cdd:cd00030  81 EVEIPLSELLDSGKEgELWLPL 102

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.

Pssm-ID: 175992 [Multi-domain] Cd Length: 131 Bit Score: 105.81 E-value: 1.03e-26

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 118 GEIHLRLEVVPGvhasRLRCAVLEARDLAPKDRNGASDPFVRVHY-----NGRTQETSVVKKSCYPRWNETFDFELEKG- 191
Cdd:cd04026   2 GRIYLKISVKDN----KLTVEVREAKNLIPMDPNGLSDPYVKLKLipdpkNETKQKTKTIKKTLNPVWNETFTFDLKPAd 77

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 84993718 192 ASEALLVEAWDWDLVSRNDFLGKVAVNVQRLCSaQQEEGWFRL 234
Cdd:cd04026  78 KDRRLSIEVWDWDRTTRNDFMGSLSFGVSELIK-MPVDGWYKL 119

Ras-GTPase Activating Domain of DAB2IP and similar proteins; The DAB2IP family of Ras GTPase-activating proteins includes DAB2IP, nGAP, and Syn GAP. Disabled 2 interactive protein, (DAB2IP; also known as ASK-interacting protein 1 (AIP1)), is a member of the GTPase-activating proteins, down-regulates Ras-mediated signal pathways, and mediates TNF-induced activation of ASK1-JNK signaling pathways. The mechanism by which TNF signaling is coupled to DAB2IP is not known.

Pssm-ID: 213338 Cd Length: 324 Bit Score: 111.52 E-value: 1.11e-26

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 262 VLPSVCYQPLVQLLCQEVKlgtqgpgRLIPVIEETTSAECRQEVATTLLKLFLGQGLAKDFLDLLFQLELGRTSEANTLF 341
Cdd:cd05136   7 ILPLEVYKEFLEYLTNNYL-------DLCEVLEPVLSVKAKEELATALVHILQSTGKAKEFLTDLVMAEVDRLDDEHLIF 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 342 RSNSLASKSMESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVevkdvgcsglhrpqTEAEVLEQSAQTLRAHLVA 421
Cdd:cd05136  80 RGNTLATKAMEAYLKLVGQKYLQETLGEFIRALYESEEDCEVDPSKC--------------PPSASLSRNQANLRRSVEL 145

                       170       180       190
                ....*....|....*....|....*....|
gi 84993718 422 LLSAICRSVRTCPAIIRATFRQLFRRVRER 451
Cdd:cd05136 146 AWCKILSSHCVFPRELREVFSSWRERLEER 175

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.

Pssm-ID: 214577 [Multi-domain] Cd Length: 101 Bit Score: 101.80 E-value: 1.18e-25

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718    134 RLRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQE---TSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRND 210
Cdd:smart00239   1 TLTVKIISARNLPPKDKGGKSDPYVKVSLDGDPKEkkkTKVVKNTLNPVWNETFEFEVPPPELAELEIEVYDKDRFGRDD 80

                           90       100
                   ....*....|....*....|.
gi 84993718    211 FLGKVAVNVQRLCSAQQEEGW 231
Cdd:smart00239  81 FIGQVTIPLSDLLLGGRHEKL 101

C2 domain;

Pssm-ID: 425499 [Multi-domain] Cd Length: 104 Bit Score: 98.93 E-value: 9.48e-25

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718     7 LSIRIVEGKNLPAKDITGSSDPYCIVKV-DNEPIIRTATVWKTLCPFWGEDYQVHLPPTFH-TVAFYVMDEDALSRDDVI 84
Cdd:pfam00168   3 LTVTVIEAKNLPPKDGNGTSDPYVKVYLlDGKQKKKTKVVKNTLNPVWNETFTFSVPDPENaVLEIEVYDYDRFGRDDFI 82

                          90       100
                  ....*....|....*....|...
gi 84993718    85 GKVCLTRDALASHpKGFSGWTHL 107
Cdd:pfam00168  83 GEVRIPLSELDSG-EGLDGWYPL 104

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.

Pssm-ID: 175973 [Multi-domain] Cd Length: 102 Bit Score: 98.29 E-value: 1.99e-24

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHL-PPTFHTVAFYVMDEDALSRDDVIG 85
Cdd:cd00030   1 LRVTVIEARNLPAKDLNGKSDPYVKVSLGGKQKFKTKVVKNTLNPVWNETFEFPVlDPESDTLTVEVWDKDRFSKDDFLG 80

                        90
                ....*....|....*....
gi 84993718  86 KVCLTRDALASHPKGFSGW 104
Cdd:cd00030  81 EVEIPLSELLDSGKEGELW 99

Ras-GTPase Activating Domain of RASA3; RASA3 (or GAP1_IP4BP) is a member of the GAP1 family and has been shown to specifically bind 1,3,4,5-tetrakisphosphate (IP4). Thus, RASA3 may function as an IP4 receptor. The members of GAP1 family are characterized by a conserved domain structure comprising N-terminal tandem C2 domains, a highly conserved central RasGAP domain, and a C-terminal pleckstrin-homology domain that is associated with a Bruton's tyrosine kinase motif. Purified RASA3 stimulates GAP activity on Ras with about a five-fold lower potency than p120RasGAP, but shows no GAP-stimulating activity at all against Rac or Rab3A.

Pssm-ID: 213336 Cd Length: 269 Bit Score: 102.02 E-value: 7.48e-24

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 301 CR--QEVATTLLKLFLGQGLAKDFLDLLFQLELGRTSEANTLFRSNSLASKSMESFLKVAGMRYLHGILGPIIDRVFEEK 378
Cdd:cd05134  32 CRekQEAAIPLVRLFLHYGKIVPFISAIASAEVNRTQDPNTIFRGNSLTSKCIDETMKLAGMHYLQVTLKPIIDEICQEH 111

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 379 KYVELDPSKVEvkdvgcsglhrpqtEAEVLEQSAQTLRAHLVALLSAICRSVRTCPAIIRATFRQLFRRVRERF---PNA 455
Cdd:cd05134 112 KPCEIDPVKLK--------------DGENLENNRENLRQYVDRIFRVITKSGVSCPTVMCDIFFSLRESAAKRFqvdPDV 177


                ....*..
gi 84993718 456 QHQAVQN 462
Cdd:cd05134 178 RYTAVSS 184

Bruton's tyrosine kinase pleckstrin homology (PH) domain; Btk is a member of the Tec family of cytoplasmic protein tyrosine kinases that includes BMX, IL2-inducible T-cell kinase (Itk) and Tec. Btk plays a role in the maturation of B cells. Tec proteins general have an N-terminal PH domain, followed by a Tek homology (TH) domain, a SH3 domain, a SH2 domain and a kinase domain. The Btk PH domain binds phosphatidylinositol 3,4,5-trisphosphate and responds to signalling via phosphatidylinositol 3-kinase. The PH domain is also involved in membrane anchoring which is confirmed by the discovery of a mutation of a critical arginine residue in the BTK PH domain. This results in severe human immunodeficiency known as X-linked agammaglobulinemia (XLA) in humans and a related disorder is mice.PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 269944 [Multi-domain] Cd Length: 140 Bit Score: 97.30 E-value: 1.19e-23

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 522 KEGpLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKST---FIKLASIRAAEKVE-EKSFGSSHIMQVIYADD 597
Cdd:cd01238   1 LEG-LLVKRSQGKKRFGPVNYKERWFVLTKSSLSYYEGDGEKRGKekgSIDLSKVRCVEEVKdEAFFERKYPFQVVYDDY 79

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 84993718 598 vgraqTVYLQCKCVNELNQWLSALRKASTNNRGLLRSYHPGIFRGDKWSCCHQKDKTDQGCDKT 661
Cdd:cd01238  80 -----TLYVFAPSEEDRDEWIAALRKVCRNNSNLHDKYHPGFWTGGKWSCCGQTSKSAPGCQPA 138

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.

Pssm-ID: 214577 [Multi-domain] Cd Length: 101 Bit Score: 93.71 E-value: 6.07e-23

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718      6 SLSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPII--RTATVWKTLCPFWGEDYQVHL-PPTFHTVAFYVMDEDALSRDD 82
Cdd:smart00239   1 TLTVKIISARNLPPKDKGGKSDPYVKVSLDGDPKEkkKTKVVKNTLNPVWNETFEFEVpPPELAELEIEVYDKDRFGRDD 80

                           90
                   ....*....|....*..
gi 84993718     83 VIGKVCLTRDALASHPK 99
Cdd:smart00239  81 FIGQVTIPLSDLLLGGR 97

C2 domain fourth repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the fifth C2 repeat, C2E, and has a type-II topology.

Pssm-ID: 176005 [Multi-domain] Cd Length: 115 Bit Score: 89.16 E-value: 3.53e-21

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNGASDPFVRVHYNGRT-QETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRNDFLG 213
Cdd:cd04040   1 LTVDVISAENLPSADRNGKSDPFVKFYLNGEKvFKTKTIKKTLNPVWNESFEVPVPSRVRAVLKVEVYDWDRGGKDDLLG 80


                ....*....
gi 84993718 214 KVAVNVQRL 222
Cdd:cd04040  81 SAYIDLSDL 89

Ras-GTPase Activating Domain of CLA2/BUD2; CLA2/BUD2 functions as a GTPase-activating protein (GAP) for BUD1/RSR1 and is necessary for proper bud-site selection in yeast. BUD2 has sequence similarity to the catalytic domain of RasGAPs, and stimulates the hydrolysis of BUD1-GTP to BUD1-GDP. Elimination of Bud2p activity by mutation causes a random budding pattern with no growth defect. Overproduction of Bud2p also alters the budding pattern.

Pssm-ID: 213339 [Multi-domain] Cd Length: 356 Bit Score: 94.55 E-value: 8.90e-21

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 255 VRLRDETVLPSVCYQPLVQLLcqevklgTQGPGRLIPVIEETTSAECRQEVATTLLKLFLGQGLAKDFLDLLFQLEL--- 331
Cdd:cd05137   2 VRLDENVVLPSKNYKPLEELL-------HNFDLGLTLQIAELVPGDKLERLSEILLDIFQASGREDEWFMALVEDEIdgi 74

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 332 ----------GRTS--EANTLFRSNSLASKSMESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVEVKDvgcsglh 399
Cdd:cd05137  75 dkstsknkdmGKSSnnEANLLFRGNSLLTKSLEKYMRRIGKEYLEKSIGDVIRKICEENKDCEVDPSRVKESD------- 147

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 400 rPQTEAEVLEQSAQTLRAHLVALLSAICRSVRTCPAIIRATFRQlFRRVRE---------------------RF------ 452
Cdd:cd05137 148 -SIEKEEDLEENWENLISLTEEIWNSIYITSNDCPPELRKILKH-IRAKVEdrygdflrtvtlnsvsgflflRFfcpail 225

                       250       260       270       280       290       300
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 84993718 453 -------------PNAQH------QAVQNIGNMDTpvSRAKESWMEPLQPTVRQGVAQLKDFI 496
Cdd:cd05137 226 npklfgllkdhprPRAQRtltliaKVLQNLANLTT--FGQKEPWMEPMNEFLTTHREELKDYI 286

Ras-GTPase Activating Domain of RASA2; RASA2 (or GAP1(m)) is a member of the GAP1 family of Ras GTPase-activating proteins that includes GAP1_IP4BP (or RASA3), CAPRI, and RASAL. In vitro, RASA2 has been shown to bind inositol 1,3,4,5-tetrakisphosphate (IP4), the water soluble inositol head group of the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3). In vivo studies also demonstrated that RASA2 binds PIP3, and it is recruited to the plasma membrane following agonist stimulation of PI 3-kinase. Furthermore, the membrane translocation is a consequence of the ability of its pleckstrin homology (PH) domain to bind PIP3.

Pssm-ID: 213342 Cd Length: 272 Bit Score: 91.49 E-value: 2.62e-20

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 265 SVCYQPLVQLLCQ--EVKLGTQGPGRLIPVIeettsaeCRQ--EVATTLLKLFLGQGLAKDFLDLLFQLELGRTSEANTL 340
Cdd:cd05394   1 SACYTSLRNLLLKspDVKPISASAAHILGEI-------CRDkyDAVLPLVRLLLHHNKLVPFVAAVAALDLKDTQEANTI 73

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 341 FRSNSLASKSMESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVEvkdvgcsglhrpqtEAEVLEQSAQTLRAHLV 420
Cdd:cd05394  74 FRGNSLATRCLDEMMKIVGKHYLKVTLKPVLDEICESPKPCEIDPIKLK--------------EGDNVENNKENLRYYVD 139

                       170       180       190
                ....*....|....*....|....*....|....*..
gi 84993718 421 ALLSAICRSVRTCPAIIRATFRQLFRRVRERFPNAQH 457
Cdd:cd05394 140 KVFFSIVKSSMSCPTLMCDVFRSLRHLAVKRFPNDPH 176

Ras-GTPase Activating Domain of proteins similar to neurofibromin; Neurofibromin-like proteins include the Saccharomyces cerevisiae RasGAP proteins Ira1 and Ira2, the closest homolog of neurofibromin, which is responsible for the human autosomal dominant disease neurofibromatosis type I (NF1). The RasGAP Ira1/2 proteins are negative regulators of the Ras-cAMP signaling pathway and conserved from yeast to human. In yeast Ras proteins are activated by GEFs, and inhibited by two GAPs, Ira1 and Ira2. Ras proteins activate the cAMP/protein kinase A (PKA) pathway, which controls metabolism, stress resistance, growth, and meiosis. Recent studies showed that the kelch proteins Gpb1 and Gpb2 inhibit Ras activity via association with Ira1 and Ira2. Gpb1/2 bind to a conserved C-terminal domain of Ira1/2, and loss of Gpb1/2 results in a destabilization of Ira1 and Ira2, leading to elevated levels of Ras2-GTP and uninhibited cAMP-PKA signaling. Since the Gpb1/2 binding domain on Ira1/2 is conserved in the human neurofibromin protein, the studies suggest that an analogous signaling mechanism may contribute to the neoplastic development of NF1.

Pssm-ID: 213341 Cd Length: 317 Bit Score: 82.33 E-value: 6.36e-17

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 273 QLLCQEVKLGTQGPGrLIPVIEETTSAECRQEVATTLLKLFLGQGLAKDFLDLLFQLELGRTSEANTLFRSNSLASKSME 352
Cdd:cd05392   4 EAYDELLELLIEDPQ-LLLAIAEVCPSSEVDLLAQSLLNLFETRNRLLPLISWLIEDEISHTSRAADLFRRNSVATRLLT 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 353 SFLKVAGMRYLHGILGPIIDRVFEEKKYVELDpskvevkdvgcsglhRPQTEAEVLEQSAQTLRAHLVALLSAICRSVRT 432
Cdd:cd05392  83 LYAKSVGNKYLRKVLRPLLTEIVDNKDYFEVE---------------KIKPDDENLEENADLLMKYAQMLLDSITDSVDQ 147

                       170       180
                ....*....|....*....|....*...
gi 84993718 433 CPAIIRATFRQLFRRVRERFPNAQHQAV 460
Cdd:cd05392 148 LPPSFRYICNTIYESVSKKFPDAALIAV 175

Ras-GTPase Activating Domain of p120; p120GAP is a negative regulator of Ras that stimulates hydrolysis of bound GTP to GDP. Once the Ras regulator p120GAP, a member of the GAP protein family, is recruited to the membrane, it is transiently immobilized to interact with Ras-GTP. The down-regulation of Ras by p120GAP is a critical step in the regulation of many cellular processes, which is disrupted in approximately 30% of human cancers. p120GAP contains SH2, SH3, PH, calcium- and lipid-binding domains, suggesting its involvement in a complex network of cellular interactions in vivo.

Pssm-ID: 213340 Cd Length: 328 Bit Score: 82.15 E-value: 8.25e-17

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 259 DETVLPSVCYQPLVQLLCQEVKLGTQGPGRLipvieettsaeCRQE---VATTLLKLFLGQGLAKDFLDLLFQLELGRTS 335
Cdd:cd05391   1 MEKIMPEEEYSELKELILQKELHVVYALAHV-----------CGQDrtlLASILLRIFRHEKLESLLLRTLNDREISMED 69

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 336 EANTLFRSNSLASKSMESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVEVKDVGCSGLhrpqteaevleqsaQTL 415
Cdd:cd05391  70 EATTLFRATTLASTLMEQYMKATATPFVHHALKDTILKILESKQSCELNPSKLEKNEDVNTNL--------------EHL 135

                       170       180       190       200
                ....*....|....*....|....*....|....*....|.
gi 84993718 416 RAHLVALLSAICRSVRTCPAIIRATFRQLFRRVRERFPNAQ 456
Cdd:cd05391 136 LNILSELVEKIFMAAEILPPTLRYIYGCLQKSVQQKWPTNT 176

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+.

Pssm-ID: 175997 [Multi-domain] Cd Length: 125 Bit Score: 76.90 E-value: 1.20e-16

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 131 HASRLRCAVLEARDLAPKDRNGASDPFVRVH-YNGRTQE----TSVVKKSCYPRWNETFDF------ELEkgaSEALLVE 199
Cdd:cd04031  14 VTSQLIVTVLQARDLPPRDDGSLRNPYVKVYlLPDRSEKskrrTKTVKKTLNPEWNQTFEYsnvrreTLK---ERTLEVT 90

                        90       100       110
                ....*....|....*....|....*....|....*...
gi 84993718 200 AWDWDLVSRNDFLGKVAVNVQrlcSAQQEEG--WFRLQ 235
Cdd:cd04031  91 VWDYDRDGENDFLGEVVIDLA---DALLDDEphWYPLQ 125

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

Pssm-ID: 176070 [Multi-domain] Cd Length: 110 Bit Score: 75.42 E-value: 2.12e-16

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLAPKDR-NGASDPFVRVHYNGRTQETSVVKKSCYPRWN-ETFDFEL--EKGASEALLVEAWDWDLVSRNDFLGK 214
Cdd:cd08688   5 VVAARDLPVMDRsSDLTDAFVEVKFGSTTYKTDVVKKSLNPVWNsEWFRFEVddEELQDEPLQIRVMDHDTYSANDAIGK 84

                        90       100
                ....*....|....*....|.
gi 84993718 215 VAVNVQRLC---SAQQEEGWF 232
Cdd:cd08688  85 VYIDLNPLLlkdSVSQISGWF 105

C2 domain fourth repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the fifth C2 repeat, C2E, and has a type-II topology.

Pssm-ID: 176005 [Multi-domain] Cd Length: 115 Bit Score: 74.14 E-value: 7.49e-16

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHLPPTFHT-VAFYVMDEDALSRDDVIG 85
Cdd:cd04040   1 LTVDVISAENLPSADRNGKSDPFVKFYLNGEKVFKTKTIKKTLNPVWNESFEVPVPSRVRAvLKVEVYDWDRGGKDDLLG 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 84993718  86 KVCLTrdalashpkgfsgwthLVEVDPNEEVQGEIHLRLE 125
Cdd:cd04040  81 SAYID----------------LSDLEPEETTELTLPLDGQ 104

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

Pssm-ID: 175990 [Multi-domain] Cd Length: 128 Bit Score: 74.38 E-value: 9.16e-16

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDR--NGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRNDFL 212
Cdd:cd04024   3 LRVHVVEAKDLAAKDRsgKGKSDPYAILSVGAQRFKTQTIPNTLNPKWNYWCEFPIFSAQNQLLKLILWDKDRFAGKDYL 82

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 84993718 213 GKVAVNVQRLCSA---QQEEGWFRLQPDQSKSRQGKGNLGSLQL 253
Cdd:cd04024  83 GEFDIALEEVFADgktGQSDKWITLKSTRPGKTSVVSGEIHLQF 126

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

Pssm-ID: 175999 [Multi-domain] Cd Length: 133 Bit Score: 73.54 E-value: 1.92e-15

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNGASDPFVRVH-YNGRTQ------ETSVVKKSCYPRWNETFDFELEKGASEaLLVEAWDWDLVS 207
Cdd:cd04033   2 LRVKVLAGIDLAKKDIFGASDPYVKISlYDPDGNgeidsvQTKTIKKTLNPKWNEEFFFRVNPREHR-LLFEVFDENRLT 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 84993718 208 RNDFLGKVAVNVQRLCSAQQEEGW------FRLQPDQSKSRQgKGNL 248
Cdd:cd04033  81 RDDFLGQVEVPLNNLPTETPGNERrytfkdYLLRPRSSKSRV-KGHL 126

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

Pssm-ID: 175999 [Multi-domain] Cd Length: 133 Bit Score: 72.77 E-value: 4.02e-15

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYC---IVKVDNEPII---RTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDALSR 80
Cdd:cd04033   2 LRVKVLAGIDLAKKDIFGASDPYVkisLYDPDGNGEIdsvQTKTIKKTLNPKWNEEFFFRVNPREHRLLFEVFDENRLTR 81

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 84993718  81 DDVIGKVCLTRDAL-ASHPKGFSGWTH----LVEVDPNEEVQGEIHLRLEVV 127
Cdd:cd04033  82 DDFLGQVEVPLNNLpTETPGNERRYTFkdylLRPRSSKSRVKGHLRLYMAYL 133

GTPase activating protein 1 m pleckstrin homology (PH) domain; GAP1(m) (also called RASA2/RAS p21 protein activator (GTPase activating protein) 2) is a member of the GAP1 family of GTPase-activating proteins, along with RASAL1, GAP1(IP4BP), and CAPRI. With the notable exception of GAP1(m), they all possess an arginine finger-dependent GAP activity on the Ras-related protein Rap1. GAP1(m) contains two C2 domains, a PH domain, a RasGAP domain, and a BTK domain. Its C2 domains, like those of GAP1IP4BP, do not contain the C2 motif that is known to be required for calcium-dependent phospholipid binding. GAP1(m) is regulated by the binding of its PH domains to phophoinositides, PIP3 (phosphatidylinositol 3,4,5-trisphosphate). It suppresses RAS, enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, allowing control of cellular proliferation and differentiation. GAP1(m) binds inositol tetrakisphosphate (IP4). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 241521 Cd Length: 133 Bit Score: 72.28 E-value: 5.91e-15

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 521 VKEGPLFiHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIRAAEKVEEKSFGSSHIMQVIYADdvgr 600
Cdd:cd13370  17 LKEGEMH-KRAQGRTRIGKKNFKKRWFCLTSRELTYHKQKGKEAIFTIPVKNILAVEKLEESAFNKKNMFQVIHSE---- 91

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 84993718 601 aQTVYLQCKCVNELNQWLSALRKASTNNRGLLRSYHPGIFRG 642
Cdd:cd13370  92 -KPLYVQANNCVEANEWIEVLSRVSRCNQKRLSFYHPSAYLG 132

C2 domain second repeat in Munc13 (mammalian uncoordinated)-like proteins; C2-like domains are thought to be involved in phospholipid binding in a Ca2+ independent manner in both Unc13 and Munc13. Caenorabditis elegans Unc13 has a central domain with sequence similarity to PKC, which includes C1 and C2-related domains. Unc13 binds phorbol esters and DAG with high affinity in a phospholipid manner. Mutations in Unc13 results in abnormal neuronal connections and impairment in cholinergic neurotransmission in the nematode. Munc13 is the mammalian homolog which are expressed in the brain. There are 3 isoforms (Munc13-1, -2, -3) and are thought to play a role in neurotransmitter release and are hypothesized to be high-affinity receptors for phorbol esters. Unc13 and Munc13 contain both C1 and C2 domains. There are two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. Munc13 interacts with syntaxin, synaptobrevin, and synaptotagmin suggesting a role for these as scaffolding proteins. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

Pssm-ID: 175976 [Multi-domain] Cd Length: 133 Bit Score: 72.27 E-value: 5.99e-15

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 134 RLRCAVLEARDLAPKDRNGASDPFVRVH------YNG-RTQETSVVKKSCYPRWNETFDFEL------EKGAseALLVEA 200
Cdd:cd04009  17 SLRVEILNARNLLPLDSNGSSDPFVKVEllprhlFPDvPTPKTQVKKKTLFPLFDESFEFNVppeqcsVEGA--LLLFTV 94

                        90       100
                ....*....|....*....|...
gi 84993718 201 WDWDLVSRNDFLGKVAVNVQRLC 223
Cdd:cd04009  95 KDYDLLGSNDFEGEAFLPLNDIP 117

C2 domain second repeat present in Synaptotagmin 1; 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 the 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. It, like synaptotagmin-2, has an N-glycosylated N-terminus. Synaptotagmin 4, a member of class 4 synaptotagmins, is located in the brain. It functions are unknown. It, like synaptotagmin-11, has an Asp to Ser substitution in its C2A domain. 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.

Pssm-ID: 176047 [Multi-domain] Cd Length: 136 Bit Score: 71.66 E-value: 9.20e-15

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 118 GEIHLRLEVVPGvhASRLRCAVLEARDLAPKDRNGASDPFVRVH--YNGR---TQETSVVKKSCYPRWNETFDFE--LEK 190
Cdd:cd08402   2 GDICFSLRYVPT--AGKLTVVILEAKNLKKMDVGGLSDPYVKIHlmQNGKrlkKKKTTIKKRTLNPYYNESFSFEvpFEQ 79

                        90       100
                ....*....|....*....|....*..
gi 84993718 191 GASEALLVEAWDWDLVSRNDFLGKVAV 217
Cdd:cd08402  80 IQKVHLIVTVLDYDRIGKNDPIGKVVL 106

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

Pssm-ID: 176037 [Multi-domain] Cd Length: 121 Bit Score: 70.78 E-value: 1.26e-14

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRN------GASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDlVSR 208
Cdd:cd08391   3 LRIHVIEAQDLVAKDKFvgglvkGKSDPYVIVRVGAQTFKSKVIKENLNPKWNEVYEAVVDEVPGQELEIELFDED-PDK 81

                        90       100       110
                ....*....|....*....|....*....|.
gi 84993718 209 NDFLGKVAVNVQRLCSAQQEEGWFRLQPDQS 239
Cdd:cd08391  82 DDFLGRLSIDLGSVEKKGFIDEWLPLEDVKS 112

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

Pssm-ID: 176058 [Multi-domain] Cd Length: 153 Bit Score: 71.63 E-value: 1.33e-14

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNGASDPF----VRVHYNGRTQE-------------------------TSVVKKSCYPRWNETFD 185
Cdd:cd08676  30 LKVTVIEAKGLLAKDVNGFSDPYcmlgIVPASRERNSEkskkrkshrkkavlkdtvpaksikvTEVKPQTLNPVWNETFR 109

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 84993718 186 FELEKGASEALLVEAWDWDlvsrNDFLGKVAVNVQRLCSaQQEEGWFRL 234
Cdd:cd08676 110 FEVEDVSNDQLHLDIWDHD----DDFLGCVNIPLKDLPS-CGLDSWFKL 153

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

Pssm-ID: 175984 [Multi-domain] Cd Length: 135 Bit Score: 71.03 E-value: 1.38e-14

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 134 RLRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDF---ELEkGASEALL-------VEAWDW 203
Cdd:cd04017   2 QLRAYIYQARDLLAADKSGLSDPFARVSFLNQSQETEVIKETLSPTWDQTLIFdevELY-GSPEEIAqnpplvvVELFDQ 80

                        90
                ....*....|..
gi 84993718 204 DLVSRNDFLGKV 215
Cdd:cd04017  81 DSVGKDEFLGRS 92

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.

Pssm-ID: 176030 [Multi-domain] Cd Length: 133 Bit Score: 70.84 E-value: 1.64e-14

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAvlearDLAPKDRNGASDPFVRVH-----YNGRTQETSVVKKSCYPRWNETFDFELEKG--ASEALLVEAWDWDLVS 207
Cdd:cd08384  20 IRCV-----NLAAMDANGYSDPFVKLYlkpdaGKKSKHKTQVKKKTLNPEFNEEFFYDIKHSdlAKKTLEITVWDKDIGK 94

                        90       100
                ....*....|....*....|....*
gi 84993718 208 RNDFLGKVAVNVQrlCSAQQEEGWF 232
Cdd:cd08384  95 SNDYIGGLQLGIN--AKGERLRHWL 117

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.

Pssm-ID: 176032 [Multi-domain] Cd Length: 125 Bit Score: 69.67 E-value: 3.85e-14

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 118 GEIHLRLEVvpGVHASRLRCAVLEARDLAPKDRNGASDPFVRVHY---NGRTQETSVVKKSCYPRWNETFDFE---LEKG 191
Cdd:cd08386   3 GRIQFSVSY--DFQESTLTLKILKAVELPAKDFSGTSDPFVKIYLlpdKKHKLETKVKRKNLNPHWNETFLFEgfpYEKL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 84993718 192 ASEALLVEAWDWDLVSRNDFLGKVAVNVQRLCSAQQEEGWFRLQP 236
Cdd:cd08386  81 QQRVLYLQVLDYDRFSRNDPIGEVSLPLNKVDLTEEQTFWKDLKP 125

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

Pssm-ID: 176007 [Multi-domain] Cd Length: 121 Bit Score: 68.07 E-value: 1.09e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 134 RLRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETS-VVKKSCYPRWNETFDFELEKgASEALLVEAWDWDLVSRNDFL 212
Cdd:cd04042   1 QLDIHLKEGRNLAARDRGGTSDPYVKFKYGGKTVYKSkTIYKNLNPVWDEKFTLPIED-VTQPLYIKVFDYDRGLTDDFM 79

                        90
                ....*....|....*..
gi 84993718 213 GKVAVNVQRLCSAQQEE 229
Cdd:cd04042  80 GSAFVDLSTLELNKPTE 96

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

Pssm-ID: 176064 [Multi-domain] Cd Length: 126 Bit Score: 68.25 E-value: 1.24e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGASEA-----LLVEAWDWDLVSRNDFLG 213
Cdd:cd08682   5 VLQARGLLCKGKSGTNDAYVIIQLGKEKYSTSVKEKTTSPVWKEECSFELPGLLSGNgnratLQLTVMHRNLLGLDKFLG 84

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 84993718 214 KVAVNVQRLCSAQQEE--GWFRLqpdqsKSRQGKGNLGSLQLEVRL 257
Cdd:cd08682  85 QVSIPLNDLDEDKGRRrtRWFKL-----ESKPGKDDKERGEIEVDI 125

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

Pssm-ID: 176007 [Multi-domain] Cd Length: 121 Bit Score: 67.69 E-value: 1.53e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   6 SLSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDALSRDDVIG 85
Cdd:cd04042   1 QLDIHLKEGRNLAARDRGGTSDPYVKFKYGGKTVYKSKTIYKNLNPVWDEKFTLPIEDVTQPLYIKVFDYDRGLTDDFMG 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 84993718  86 KVCLTrdaLASHPKGFSGWTHLVEVDPN-EEVQGEIHLRLEVVP 128
Cdd:cd04042  81 SAFVD---LSTLELNKPTEVKLKLEDPNsDEDLGYISLVVTLTP 121

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

Pssm-ID: 176023 [Multi-domain] Cd Length: 119 Bit Score: 66.55 E-value: 3.55e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELeKGASEALLVEAWDWDLVSRNDFLGK 214
Cdd:cd08377   3 LQVKVIRASGLAAADIGGKSDPFCVLELVNARLQTHTIYKTLNPEWNKIFTFPI-KDIHDVLEVTVYDEDKDKKPEFLGK 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 84993718 215 VAVNVQRLCSAQQEegWFRLQpDQSKSRQGKGNLgSLQLEV 255
Cdd:cd08377  82 VAIPLLSIKNGERK--WYALK-DKKLRTRAKGSI-LLEMDV 118

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

Pssm-ID: 176037 [Multi-domain] Cd Length: 121 Bit Score: 65.78 E-value: 6.61e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDI------TGSSDPYCIVKVDNEpIIRTATVWKTLCPFWGEDYQVHLPPTF-HTVAFYVMDEDaLS 79
Cdd:cd08391   3 LRIHVIEAQDLVAKDKfvgglvKGKSDPYVIVRVGAQ-TFKSKVIKENLNPKWNEVYEAVVDEVPgQELEIELFDED-PD 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 84993718  80 RDDVIGkvCLTRDALASHPKGFSG-WTHLVEVDpneevQGEIHLRLE 125
Cdd:cd08391  81 KDDFLG--RLSIDLGSVEKKGFIDeWLPLEDVK-----SGRLHLKLE 120

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.

Pssm-ID: 175987 [Multi-domain] Cd Length: 162 Bit Score: 66.58 E-value: 9.78e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 118 GEIHLRLE-VVPGVHASR---------LRCAVLEARDLAPKDRNGASDPFVRVHY----NGRT-QETSVVKKSCYPRWNE 182
Cdd:cd04020   2 GELKVALKyVPPESEGALkskkpstgeLHVWVKEAKNLPALKSGGTSDSFVKCYLlpdkSKKSkQKTPVVKKSVNPVWNH 81

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 84993718 183 TFDFElekGASEALLVEA------WDWDLVSRNDFLGKVAVNVQRLCSAQQEEGW 231
Cdd:cd04020  82 TFVYD---GVSPEDLSQAcleltvWDHDKLSSNDFLGGVRLGLGTGKSYGQAVDW 133

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

Pssm-ID: 176050 [Multi-domain] Cd Length: 136 Bit Score: 65.52 E-value: 1.55e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 132 ASRLRCAVLEARDLAPKDRNGASDPFVRV--HYNGRTQE--TSVVKKSCY-PRWNETFDFE--LEKGASEALLVEAWDWD 204
Cdd:cd08405  14 ANRITVNIIKARNLKAMDINGTSDPYVKVwlMYKDKRVEkkKTVIKKRTLnPVFNESFIFNipLERLRETTLIITVMDKD 93

                        90
                ....*....|.
gi 84993718 205 LVSRNDFLGKV 215
Cdd:cd08405  94 RLSRNDLIGKI 104

C2 domain second repeat present in RAS p21 protein activator 3 (RasA3); RasA3 are members of GTPase activating protein 1 (GAP1), a Ras-specific GAP, which suppresses 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. RasA3 contains an N-terminal C2 domain, a Ras-GAP domain, a plextrin homology (PH)-like domain, and a Bruton's Tyrosine Kinase (BTK) zinc binding 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. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 175977 [Multi-domain] Cd Length: 148 Bit Score: 65.50 E-value: 1.96e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 134 RLRCAVLEARDLAPKdrNGASDPFVRV---HYNGR--TQETSVVKKSCYPRWNETFDFELEKGASEA------------- 195
Cdd:cd04010   1 KLSVRVIECSDLALK--NGTCDPYASVtliYSNKKqdTKRTKVKKKTNNPQFDEAFYFDVTIDSSPEkkqfempeedaek 78

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 84993718 196 --LLVEAWDWDLVSRNDFLGKVAVNVQRL-CSAQQEEGWFRLQPDQSKS-----RQGKGN-LGSLQLEV 255
Cdd:cd04010  79 leLRVDLWHASMGGGDVFLGEVRIPLRGLdLQAGSHQAWYFLQPREEKStppgtRSSKDNsLGSLRLKI 147

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.

Pssm-ID: 175975 [Multi-domain] Cd Length: 134 Bit Score: 64.91 E-value: 2.32e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 118 GEIHLRLEVVPgvHASRLRCAVLEARDLAPKDRNGASDPFVRVH--YNGR---TQETSVVKKSCYPRWNETFDFELEKGA 192
Cdd:cd00276   1 GELLLSLSYLP--TAERLTVVVLKARNLPPSDGKGLSDPYVKVSllQGGKklkKKKTSVKKGTLNPVFNEAFSFDVPAEQ 78

                        90       100
                ....*....|....*....|....*..
gi 84993718 193 SE--ALLVEAWDWDLVSRNDFLGKVAV 217
Cdd:cd00276  79 LEevSLVITVVDKDSVGRNEVIGQVVL 105

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

Pssm-ID: 176050 [Multi-domain] Cd Length: 136 Bit Score: 63.98 E-value: 4.00e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   5 SSLSIRIVEGKNLPAKDITGSSDPYciVKV-----DNEPIIRTATVWK-TLCPFWGEDYQVHLPptFH-----TVAFYVM 73
Cdd:cd08405  15 NRITVNIIKARNLKAMDINGTSDPY--VKVwlmykDKRVEKKKTVIKKrTLNPVFNESFIFNIP--LErlretTLIITVM 90

                        90
                ....*....|....*.
gi 84993718  74 DEDALSRDDVIGKVCL 89
Cdd:cd08405  91 DKDRLSRNDLIGKIYL 106

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

Pssm-ID: 176003 [Multi-domain] Cd Length: 145 Bit Score: 63.88 E-value: 5.44e-12

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 84993718   7 LSIRIVEGKNLPAKDITgSSDPYCIVKVDNEPIiRTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDALSRDDVIG 85
Cdd:cd04038   4 LKVRVVRGTNLAVRDFT-SSDPYVVLTLGNQKV-KTRVIKKNLNPVWNEELTLSVPNPMAPLKLEVFDKDTFSKDDSMG 80

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

Pssm-ID: 176023 [Multi-domain] Cd Length: 119 Bit Score: 63.09 E-value: 5.76e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNEpIIRTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDALSRDDVIGK 86
Cdd:cd08377   3 LQVKVIRASGLAAADIGGKSDPFCVLELVNA-RLQTHTIYKTLNPEWNKIFTFPIKDIHDVLEVTVYDEDKDKKPEFLGK 81


                .
gi 84993718  87 V 87
Cdd:cd08377  82 V 82

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

Pssm-ID: 214574 [Multi-domain] Cd Length: 102 Bit Score: 62.57 E-value: 6.27e-12

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718    520 PVKEGPLFIhrtkgKGPLASSSFKKLYFSLTTEALSFAKTSSSKKST----FIKLASIRAAEKVEEKSFGSSHIMQVIYA 595
Cdd:smart00233   1 VIKEGWLYK-----KSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYkpkgSIDLSGCTVREAPDPDSSKKPHCFEIKTS 75

                           90       100       110
                   ....*....|....*....|....*....|
gi 84993718    596 DDvgraQTVYLQCKCVNELNQWLSALRKAS 625
Cdd:smart00233  76 DR----KTLLLQAESEEEREKWVEALRKAI 101

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.

Pssm-ID: 175989 [Multi-domain] Cd Length: 127 Bit Score: 63.12 E-value: 6.80e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGA---SEALLVEAW-DWDLVSRNDFLGK 214
Cdd:cd04022   6 VVDAQDLMPKDGQGSSSAYVELDFDGQKKRTRTKPKDLNPVWNEKLVFNVSDPSrlsNLVLEVYVYnDRRSGRRRSFLGR 85

                        90
                ....*....|....*....
gi 84993718 215 VAVNVQRLCSaQQEEGWFR 233
Cdd:cd04022  86 VRISGTSFVP-PSEAVVQR 103

BTK motif; Zinc-binding motif containing conserved cysteines and a histidine. Always found C-terminal to PH domains. The crystal structure shows this motif packs against the PH domain. The PH+Btk module pair has been called the Tec homology (TH) region.

Pssm-ID: 459937 Cd Length: 30 Bit Score: 59.85 E-value: 8.14e-12

                          10        20        30
                  ....*....|....*....|....*....|
gi 84993718   634 SYHPGIFRGDKWSCCHQKDKTDQGCDKTHS 663
Cdd:pfam00779   1 KYHPGAFVDGKWLCCKQTDKNAPGCSPVTS 30

C2 domain second repeat present in Synaptotagmin 17; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. 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 second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 176055 [Multi-domain] Cd Length: 135 Bit Score: 62.99 E-value: 1.18e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 118 GEIHLRLEVVPGvhASRLRCAVLEARDLAPKDRNGASDPFVRVHY-NG----RTQETSVVKKSCYPRWNETFDFEL--EK 190
Cdd:cd08410   1 GELLLSLNYLPS--AGRLNVDIIRAKQLLQTDMSQGSDPFVKIQLvHGlkliKTKKTSCMRGTIDPFYNESFSFKVpqEE 78

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 84993718 191 GASEALLVEAWDWDLVSRNDFLGKVAVNvQRLCSAQQEEGWFRL 234
Cdd:cd08410  79 LENVSLVFTVYGHNVKSSNDFIGRIVIG-QYSSGPSETNHWRRM 121

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.

Pssm-ID: 176032 [Multi-domain] Cd Length: 125 Bit Score: 62.35 E-value: 1.28e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   5 SSLSIRIVEGKNLPAKDITGSSDPYciVKV----DNEPIIRTATVWKTLCPFWGEdyqvhlppTFH------------TV 68
Cdd:cd08386  16 STLTLKILKAVELPAKDFSGTSDPF--VKIyllpDKKHKLETKVKRKNLNPHWNE--------TFLfegfpyeklqqrVL 85

                        90       100
                ....*....|....*....|.
gi 84993718  69 AFYVMDEDALSRDDVIGKVCL 89
Cdd:cd08386  86 YLQVLDYDRFSRNDPIGEVSL 106

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.

Pssm-ID: 176031 [Multi-domain] Cd Length: 124 Bit Score: 62.28 E-value: 1.32e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   4 RSSLSIRIVEGKNLPAKDITGSSDPYciVKV----DNEPIIRTATVWKTLCPFWGEDYQVHLPP---TFHTVAFYVMDED 76
Cdd:cd08385  15 SNQLTVGIIQAADLPAMDMGGTSDPY--VKVyllpDKKKKFETKVHRKTLNPVFNETFTFKVPYselGNKTLVFSVYDFD 92

                        90
                ....*....|....
gi 84993718  77 ALSRDDVIGKVCLT 90
Cdd:cd08385  93 RFSKHDLIGEVRVP 106

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

Pssm-ID: 176022 [Multi-domain] Cd Length: 116 Bit Score: 61.50 E-value: 2.27e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRNDFLGKVAVN 218
Cdd:cd08376   6 LVEGKNLPPMDDNGLSDPYVKFRLGNEKYKSKVCSKTLNPQWLEQFDLHLFDDQSQILEIEVWDKDTGKKDEFIGRCEID 85


                ....
gi 84993718 219 VQRL 222
Cdd:cd08376  86 LSAL 89

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

Pssm-ID: 175990 [Multi-domain] Cd Length: 128 Bit Score: 60.90 E-value: 4.18e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDI--TGSSDPYCIVKVdNEPIIRTATVWKTLCPFWgeDYQVHLPPTFH---TVAFYVMDEDALSRD 81
Cdd:cd04024   3 LRVHVVEAKDLAAKDRsgKGKSDPYAILSV-GAQRFKTQTIPNTLNPKW--NYWCEFPIFSAqnqLLKLILWDKDRFAGK 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 84993718  82 DVIGKVCLTRDALASHPKG--FSGWTHLVEVDPNEE--VQGEIHLRL 124
Cdd:cd04024  80 DYLGEFDIALEEVFADGKTgqSDKWITLKSTRPGKTsvVSGEIHLQF 126

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.

Pssm-ID: 176039 [Multi-domain] Cd Length: 125 Bit Score: 60.91 E-value: 4.72e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 117 QGEIHLRLEVVPGvhASRLRCAVLEARDLAPKDRN-GASDPFVRVHY---NGR--TQETSVVKKSCYPRWNETFDFELEK 190
Cdd:cd08393   1 QGSVQFALDYDPK--LRELHVHVIQCQDLAAADPKkQRSDPYVKTYLlpdKSNrgKRKTSVKKKTLNPVFNETLRYKVER 78

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 84993718 191 GA--SEALLVEAWDWDLVSRNDFLGKVAVNVQRLCSAQQEEGWFRLQ 235
Cdd:cd08393  79 EElpTRVLNLSVWHRDSLGRNSFLGEVEVDLGSWDWSNTQPTWYPLQ 125

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

Pssm-ID: 176002 [Multi-domain] Cd Length: 124 Bit Score: 60.64 E-value: 4.85e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 136 RCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETS--VVKKSCYPRWNETFDFELE-KGASEaLLVEAWDWDLVSRNDFL 212
Cdd:cd04037   3 RVYVVRARNLQPKDPNGKSDPYLKIKLGKKKINDRdnYIPNTLNPVFGKMFELEATlPGNSI-LKISVMDYDLLGSDDLI 81


                ..
gi 84993718 213 GK 214
Cdd:cd04037  82 GE 83

GAP1(IP4BP) pleckstrin homology (PH) domain; GAP1 (also called IP4BP, RASA3/Ras GTPase-activating protein 3, and RAS p21 protein activator (GTPase activating protein) 3/GAPIII/MGC46517/MGC47588)) is a member of the GAP1 family of GTPase-activating proteins, along with RASAL1, GAP1(m), and CAPRI. With the notable exception of GAP1(m), they all possess an arginine finger-dependent GAP activity on the Ras-related protein Rap1. GAP1(IP4BP) contains two C2 domains, a PH domain, a RasGAP domain, and a BTK domain. Its C2 domains, like those of GAP1M, do not contain the C2 motif that is known to be required for calcium-dependent phospholipid binding. GAP1(IP4BP) is regulated by the binding of its PH domains to phophoinositides, PIP3 (phosphatidylinositol 3,4,5-trisphosphate) and PIP2 (phosphatidylinositol 4,5-bisphosphate). It suppresses RAS, enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, allowing control of cellular proliferation and differentiation. GAP1(IP4BP) binds tyrosine-protein kinase, HCK. Members here include humans, chickens, frogs, and fish. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 241522 Cd Length: 125 Bit Score: 60.05 E-value: 9.39e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 521 VKEGpLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIRAAEKVEEKSFGSSHIMQVIYADdvgr 600
Cdd:cd13371  17 LKEG-FMIKRAQGRKRFGMKNFKKRWFRLTNHEFTYHKSKGDHPLCSIPIENILAVERLEEESFKMKNMFQVIQPE---- 91

                        90       100       110
                ....*....|....*....|....*....|....*
gi 84993718 601 aQTVYLQCKCVNELNQWLSALRKASTNNRGLLRSY 635
Cdd:cd13371  92 -RALYIQANNCVEAKDWIDILTKVSQCNKKRLTVY 125

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

Pssm-ID: 176003 [Multi-domain] Cd Length: 145 Bit Score: 60.03 E-value: 1.38e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNGaSDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGASeALLVEAWDWDLVSRNDFLGK 214
Cdd:cd04038   4 LKVRVVRGTNLAVRDFTS-SDPYVVLTLGNQKVKTRVIKKNLNPVWNEELTLSVPNPMA-PLKLEVFDKDTFSKDDSMGE 81

                        90
                ....*....|...
gi 84993718 215 VAVNVQRLCSAQQ 227
Cdd:cd04038  82 AEIDLEPLVEAAK 94

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

Pssm-ID: 175993 [Multi-domain] Cd Length: 127 Bit Score: 59.50 E-value: 1.46e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 133 SRLRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKgASEALLVEAW--DWDLVSR-- 208
Cdd:cd04027   1 AKISITVVCAQGLIAKDKTGTSDPYVTVQVGKTKKRTKTIPQNLNPVWNEKFHFECHN-SSDRIKVRVWdeDDDIKSRlk 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 84993718 209 -------NDFLGKVAVNVQRLcsAQQEEGWFRLQPDQSKS 241
Cdd:cd04027  80 qkftresDDFLGQTIIEVRTL--SGEMDVWYNLEKRTDKS 117

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.

Pssm-ID: 176031 [Multi-domain] Cd Length: 124 Bit Score: 59.20 E-value: 1.66e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLAPKDRNGASDPFVRVHY---NGRTQETSVVKKSCYPRWNETFDF-----ELEkgaSEALLVEAWDWDLVSRND 210
Cdd:cd08385  22 IIQAADLPAMDMGGTSDPYVKVYLlpdKKKKFETKVHRKTLNPVFNETFTFkvpysELG---NKTLVFSVYDFDRFSKHD 98

                        90       100
                ....*....|....*....|....*.
gi 84993718 211 FLGKVAVNVQRLCSAQQEEGWFRLQP 236
Cdd:cd08385  99 LIGEVRVPLLTVDLGHVTEEWRDLES 124

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

Pssm-ID: 176033 [Multi-domain] Cd Length: 124 Bit Score: 58.57 E-value: 2.37e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKV--DNEPIIRTATVWKTLCPFWGEDYQVHLPPTF---HTVAFYVMDEDALSRD 81
Cdd:cd08387  18 LNVKLIQARNLQPRDFSGTADPYCKVRLlpDRSNTKQSKIHKKTLNPEFDESFVFEVPPQElpkRTLEVLLYDFDQFSRD 97


                ....*...
gi 84993718  82 DVIGKVCL 89
Cdd:cd08387  98 ECIGVVEL 105

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

Pssm-ID: 176008 [Multi-domain] Cd Length: 126 Bit Score: 58.81 E-value: 2.57e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   8 SIRIVEGKNLPAKDITGSSDPYcIVKVDN---EPIIRTATVWKTLCPFWGEDYQVHLPPTF-HTVAFYVMDEDALSRDDV 83
Cdd:cd04043   4 TIRIVRAENLKADSSNGLSDPY-VTLVDTngkRRIAKTRTIYDTLNPRWDEEFELEVPAGEpLWISATVWDRSFVGKHDL 82

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 84993718  84 IGKVCLTRDalashPKGFS--GWTHLVEVDPNeeVQGEIHLRLEV 126
Cdd:cd04043  83 CGRASLKLD-----PKRFGddGLPREIWLDLD--TQGRLLLRVSM 120

C2 domain second repeat present in Synaptotagmin 4; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 4, a member of class 4 synaptotagmins, is located in the brain. It functions are unknown. It, like synaptotagmin-11, has an Asp to Ser substitution in its C2A domain. 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.

Pssm-ID: 176049 [Multi-domain] Cd Length: 136 Bit Score: 58.98 E-value: 2.58e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 117 QGEIHLRLEVVPGVHasRLRCAVLEARDLAPKDRNGASDPFVRVH--YNGR---TQETSVVKKSCYPRWNETFDFELEKG 191
Cdd:cd08404   1 RGELLLSLCYQPTTN--RLTVVVLKARHLPKMDVSGLADPYVKVNlyYGKKrisKKKTHVKKCTLNPVFNESFVFDIPSE 78

                        90       100       110
                ....*....|....*....|....*....|....*...
gi 84993718 192 ASEALLVE--AWDWDLVSRNDFLGKVAVNVQRLCSAQQ 227
Cdd:cd08404  79 ELEDISVEflVLDSDRVTKNEVIGRLVLGPKASGSGGH 116

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

Pssm-ID: 176000 [Multi-domain] Cd Length: 123 Bit Score: 58.45 E-value: 2.91e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 131 HASRLRCAVLEARDLAPKDRNGASDPFVRVHY-----NGRTQETSVVKKSCYPRWNETFDFElekGASE------ALLVE 199
Cdd:cd04035  13 ANSALHCTIIRAKGLKAMDANGLSDPYVKLNLlpgasKATKLRTKTVHKTRNPEFNETLTYY---GITEediqrkTLRLL 89

                        90       100
                ....*....|....*....|...
gi 84993718 200 AWDWDLVsRNDFLGKVAVNVQRL 222
Cdd:cd04035  90 VLDEDRF-GNDFLGETRIPLKKL 111

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

Pssm-ID: 176070 [Multi-domain] Cd Length: 110 Bit Score: 58.09 E-value: 3.00e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKD-ITGSSDPYCIVKVDNEPIiRTATVWKTLCPFWGEDYQVhlpptFHT---------VAFYVMDED 76
Cdd:cd08688   1 LKVRVVAARDLPVMDrSSDLTDAFVEVKFGSTTY-KTDVVKKSLNPVWNSEWFR-----FEVddeelqdepLQIRVMDHD 74

                        90       100       110
                ....*....|....*....|....*....|
gi 84993718  77 ALSRDDVIGKVCLTRDALASHPKG--FSGW 104
Cdd:cd08688  75 TYSANDAIGKVYIDLNPLLLKDSVsqISGW 104

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.

Pssm-ID: 175996 [Multi-domain] Cd Length: 127 Bit Score: 58.44 E-value: 3.17e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 133 SRLRCAVLEARDLAPKDRNGASDPFVRV------HYNGRtQETSVVKKSCYPRWNETFDF-----ELEKGASEALLVEAW 201
Cdd:cd04030  16 QKLIVTVHKCRNLPPCDSSDIPDPYVRLyllpdkSKSTR-RKTSVKKDNLNPVFDETFEFpvsleELKRRTLDVAVKNSK 94

                        90       100       110
                ....*....|....*....|....*....|....
gi 84993718 202 DWdLVSRNDFLGKVAVNVQRLCSAQQEEGWFRLQ 235
Cdd:cd04030  95 SF-LSREKKLLGQVLIDLSDLDLSKGFTQWYDLT 127

C2 domain second repeat in Munc13 (mammalian uncoordinated)-like proteins; C2-like domains are thought to be involved in phospholipid binding in a Ca2+ independent manner in both Unc13 and Munc13. Caenorabditis elegans Unc13 has a central domain with sequence similarity to PKC, which includes C1 and C2-related domains. Unc13 binds phorbol esters and DAG with high affinity in a phospholipid manner. Mutations in Unc13 results in abnormal neuronal connections and impairment in cholinergic neurotransmission in the nematode. Munc13 is the mammalian homolog which are expressed in the brain. There are 3 isoforms (Munc13-1, -2, -3) and are thought to play a role in neurotransmitter release and are hypothesized to be high-affinity receptors for phorbol esters. Unc13 and Munc13 contain both C1 and C2 domains. There are two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. Munc13 interacts with syntaxin, synaptobrevin, and synaptotagmin suggesting a role for these as scaffolding proteins. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

Pssm-ID: 175976 [Multi-domain] Cd Length: 133 Bit Score: 58.02 E-value: 4.50e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   6 SLSIRIVEGKNLPAKDITGSSDPYciVKVDNEP--------IIRTATVWKTLCPFWGEDYQVHLPPTFH-----TVAFYV 72
Cdd:cd04009  17 SLRVEILNARNLLPLDSNGSSDPF--VKVELLPrhlfpdvpTPKTQVKKKTLFPLFDESFEFNVPPEQCsvegaLLLFTV 94

                        90       100       110
                ....*....|....*....|....*....|....
gi 84993718  73 MDEDALSRDDVIGKVCLtrdALASHPKGFSGWTH 106
Cdd:cd04009  95 KDYDLLGSNDFEGEAFL---PLNDIPGVEDTSSA 125

C2 domain of Perforin; Perforin contains a single copy of a C2 domain in its C-terminus and plays a role in lymphocyte-mediated cytotoxicity. Mutations in perforin leads to familial hemophagocytic lymphohistiocytosis type 2. The function of perforin is calcium dependent and the C2 domain is thought to confer this binding to target cell membranes. 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.

Pssm-ID: 175998 [Multi-domain] Cd Length: 127 Bit Score: 57.66 E-value: 5.13e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 133 SRLRCAVLEARDLapkdrNG----ASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDF---ELEKGASeaLLVEAWDWDL 205
Cdd:cd04032  28 ATLTVTVLRATGL-----WGdyftSTDGYVKVFFGGQEKRTEVIWNNNNPRWNATFDFgsvELSPGGK--LRFEVWDRDN 100

                        90       100       110
                ....*....|....*....|....*....|....
gi 84993718 206 VSRNDFLGKvavnvqrlCSAQQEEG----WFRLQ 235
Cdd:cd04032 101 GWDDDLLGT--------CSVVPEAGvhedSCQLN 126

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

Pssm-ID: 176008 [Multi-domain] Cd Length: 126 Bit Score: 57.66 E-value: 5.79e-10

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 84993718 139 VLEARDLAPKDRNGASDPFVRVHYNGRTQE---TSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRNDFLGK 214
Cdd:cd04043   7 IVRAENLKADSSNGLSDPYVTLVDTNGKRRiakTRTIYDTLNPRWDEEFELEVPAGEPLWISATVWDRSFVGKHDLCGR 85

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

Pssm-ID: 176019 [Multi-domain] Cd Length: 127 Bit Score: 57.26 E-value: 6.97e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLAPKdrNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGA--SEALLVEAWDWDLVSRNDFLGKVA 216
Cdd:cd08373   2 VVSLKNLPGL--KGKGDRIAKVTFRGVKKKTRVLENELNPVWNETFEWPLAGSPdpDESLEIVVKDYEKVGRNRLIGSAT 79


                ....*...
gi 84993718 217 VNVQRLCS 224
Cdd:cd08373  80 VSLQDLVS 87

C2 domain present in Intersectin; A single instance of the C2 domain is located C terminally in the intersectin protein. Intersectin functions as a scaffolding protein, providing a link between the actin cytoskeleton and the components of endocytosis and plays a role in signal transduction. In addition to C2, intersectin contains several additional domains including: Eps15 homology domains, SH3 domains, a RhoGEF domain, and a PH 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. The members here have topology I.

Pssm-ID: 176021 [Multi-domain] Cd Length: 136 Bit Score: 57.01 E-value: 1.20e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 134 RLRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRNDFLG 213
Cdd:cd08375  16 RLMVVIVEGRDLKPCNSNGKSDPYCEVSMGSQEHKTKVVSDTLNPKWNSSMQFFVKDLEQDVLCITVFDRDFFSPDDFLG 95


                ....*.
gi 84993718 214 KVAVNV 219
Cdd:cd08375  96 RTEIRV 101

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.

Pssm-ID: 176056 [Multi-domain] Cd Length: 123 Bit Score: 56.49 E-value: 1.39e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKD-RNGASDPFVRVHY-----NGRTQETSVVKKSCYPRWNETFDFELEKG--ASEALLVEAWDWDLV 206
Cdd:cd08521  16 LEVHIKECRNLAYADeKKKRSNPYVKVYLlpdksKQSKRKTSVKKNTTNPVFNETLKYHISKSqlETRTLQLSVWHHDRF 95

                        90       100
                ....*....|....*....|....*...
gi 84993718 207 SRNDFLGKVAVNVQRLCSAQQEEGWFRL 234
Cdd:cd08521  96 GRNTFLGEVEIPLDSWDLDSQQSEWYPL 123

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

Pssm-ID: 176022 [Multi-domain] Cd Length: 116 Bit Score: 56.11 E-value: 1.52e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNEpIIRTATVWKTLCPFWGEDYQVHL-PPTFHTVAFYVMDEDALSRDDVIG 85
Cdd:cd08376   2 VTIVLVEGKNLPPMDDNGLSDPYVKFRLGNE-KYKSKVCSKTLNPQWLEQFDLHLfDDQSQILEIEVWDKDTGKKDEFIG 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 84993718  86 KVCLTRDALaSHPKgfsgwTHLVEVdPNEEVQGEIHLRLEVVP 128
Cdd:cd08376  81 RCEIDLSAL-PREQ-----THSLEL-ELEDGEGSLLLLLTLTG 116

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

Pssm-ID: 176006 [Multi-domain] Cd Length: 111 Bit Score: 55.73 E-value: 1.81e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDI-TGSSDPYCIV--KVDNEPIIRTATVWKTLCPFWGEDYQVHLPPTFH----TVAFYVMDEDALS 79
Cdd:cd04041   3 LVVTIHRATDLPKADFgTGSSDPYVTAsfAKFGKPLYSTRIIRKDLNPVWEETWFVLVTPDEVkageRLSCRLWDSDRFT 82

                        90
                ....*....|....*....
gi 84993718  80 RDDVIGKVCLTRDALASHP 98
Cdd:cd04041  83 ADDRLGRVEIDLKELIEDR 101

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

Pssm-ID: 176028 [Multi-domain] Cd Length: 123 Bit Score: 55.78 E-value: 2.21e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 134 RLRCAVLEARDLAPKDRNGASDPFVRVHYNG-RTQETSVVKKSCYPRWNETFDFELEKgaSEALLVEAWDWDLVSRND-- 210
Cdd:cd08382   1 KVRLTVLCADGLAKRDLFRLPDPFAVITVDGgQTHSTDVAKKTLDPKWNEHFDLTVGP--SSIITIQVFDQKKFKKKDqg 78

                        90       100       110
                ....*....|....*....|....*....|....*....
gi 84993718 211 FLGKVAV---NVQRLCSAQQEEGWFR-LQPDQSKSRQGK 245
Cdd:cd08382  79 FLGCVRIranAVLPLKDTGYQRLDLRkLKKSDNLSVRGK 117

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

Pssm-ID: 176002 [Multi-domain] Cd Length: 124 Bit Score: 56.02 E-value: 2.29e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718  11 IVEGKNLPAKDITGSSDPYCIVKVDNEPI-IRTATVWKTLCPFWGEDYQVH-LPPTFHTVAFYVMDEDALSRDDVIGKVC 88
Cdd:cd04037   6 VVRARNLQPKDPNGKSDPYLKIKLGKKKInDRDNYIPNTLNPVFGKMFELEaTLPGNSILKISVMDYDLLGSDDLIGETV 85

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 275388 [Multi-domain] Cd Length: 92 Bit Score: 54.09 E-value: 4.61e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 522 KEGPLFIhrtkgKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIRAAEKVEEKSFGSS-HIMQVIYADDvgr 600
Cdd:cd00821   1 KEGYLLK-----RGGGGLKSWKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGILEVEEVSPKERpHCFELVTPDG--- 72

                        90       100
                ....*....|....*....|.
gi 84993718 601 aQTVYLQCKCVNELNQWLSAL 621
Cdd:cd00821  73 -RTYYLQADSEEERQEWLKAL 92

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

Pssm-ID: 227371 [Multi-domain] Cd Length: 1227 Bit Score: 60.16 E-value: 4.77e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718  142 ARDLAPKDRNGASDPFVRVHYNGRT-QETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSRNDFLGKVAVNVQ 220
Cdd:COG5038 1049 GENLPSSDENGYSDPFVKLFLNEKSvYKTKVVKKTLNPVWNEEFTIEVLNRVKDVLTINVNDWDSGEKNDLLGTAEIDLS 1128

                         90
                 ....*....|..
gi 84993718  221 RLcSAQQEEGWF 232
Cdd:COG5038 1129 KL-EPGGTTNSN 1139

Ras-GTPase Activating Domain of neurofibromin; Neurofibromin is the product of the neurofibromatosis type 1 gene (NF1) and shares a region of similarity with catalytic domain of the mammalian p120RasGAP protein and an extended similarity with the Saccharomyces cerevisiae RasGAP proteins Ira1 and Ira2. Neurofibromin has been shown to function as a GAP (GTPase-activating protein) which inhibits low molecular weight G proteins such as Ras by stimulating their intrinsic GTPase activity. NF1 is a common genetic disorder characterized by various symptoms ranging from predisposition for the development of tumors to learning disability or mental retardation. Loss of neurofibromin activity can be correlated to the increase in Ras-GTP concentration in neurofibromas of NF1 of patients, supporting the notion that unregulated Ras signaling may contribute to their development.

Pssm-ID: 213332 [Multi-domain] Cd Length: 332 Bit Score: 58.49 E-value: 5.06e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 300 ECRQEVATTLLKLFLGQGLAKDFLDLLFQLELGRTSEANTLFRSNSLASKSMESFLKVAGMRYLHGILGPIIDRVFE--E 377
Cdd:cd05130  37 SQMDELARVLVTLFDSKHLLYQLLWNMFSKEVELADSMQTLFRGNSLASKIMTFCFKVYGATYLQSLLEPLLRTMITssE 116

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 378 KKYVELDPSKVEVKdvgcsglhrpqteaEVLEQSAQTLRAHLVALLSAICRSVRTCPAIIRATFRQLFRRVRERFPNAQH 457
Cdd:cd05130 117 WVSYEVDPTRLEGN--------------ENLEENQRNLLQLTEKFFHAIISSSDEFPPQLRSVCHCLYQVVSHRFPNSGL 182


                ....*.
gi 84993718 458 QAVQNI 463
Cdd:cd05130 183 GAVGSA 188

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.

Pssm-ID: 176027 [Multi-domain] Cd Length: 122 Bit Score: 54.61 E-value: 5.81e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 117 QGEIHLRLEVvpgvHASRLRCAVLEARDLAPKDrNGASDPFVRVH-----YNGRTQETSVVKKSCYPRWNETFDFE---L 188
Cdd:cd08381   1 GGQVKLSISY----KNGTLFVMVMHAKNLPLLD-GSDPDPYVKTYllpdpQKTTKRKTKVVRKTRNPTFNEMLVYDglpV 75

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 84993718 189 EKGASEALLVEAWDWDLVSRNDFLGKVAVNVQRLCSAQQEEGWFRL 234
Cdd:cd08381  76 EDLQQRVLQVSVWSHDSLVENEFLGGVCIPLKKLDLSQETEKWYPL 121

PH domain; PH stands for pleckstrin homology.

Pssm-ID: 459697 [Multi-domain] Cd Length: 105 Bit Score: 54.11 E-value: 6.04e-09

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   520 PVKEGPLFIhrtkgKGPLASSSFKKLYFSLTTEALSFAKTSSSKKST----FIKLASIRAAEKVEEKSFGSSHIMQVIYa 595
Cdd:pfam00169   1 VVKEGWLLK-----KGGGKKKSWKKRYFVLFDGSLLYYKDDKSGKSKepkgSISLSGCEVVEVVASDSPKRKFCFELRT- 74

                          90       100       110
                  ....*....|....*....|....*....|
gi 84993718   596 DDVGRAQTVYLQCKCVNELNQWLSALRKAS 625
Cdd:pfam00169  75 GERTGKRTYLLQAESEEERKDWIKAIQSAI 104

C2 domain second repeat present in Synaptotagmin 1; 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 the 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. It, like synaptotagmin-2, has an N-glycosylated N-terminus. Synaptotagmin 4, a member of class 4 synaptotagmins, is located in the brain. It functions are unknown. It, like synaptotagmin-11, has an Asp to Ser substitution in its C2A domain. 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.

Pssm-ID: 176047 [Multi-domain] Cd Length: 136 Bit Score: 55.10 E-value: 6.13e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYciVKV----DNEPIIRTATVWK--TLCPFWGEDYQVHLPptFH-----TVAFYVMDE 75
Cdd:cd08402  17 LTVVILEAKNLKKMDVGGLSDPY--VKIhlmqNGKRLKKKKTTIKkrTLNPYYNESFSFEVP--FEqiqkvHLIVTVLDY 92

                        90
                ....*....|....
gi 84993718  76 DALSRDDVIGKVCL 89
Cdd:cd08402  93 DRIGKNDPIGKVVL 106

C2 domain second repeat present in Synaptotagmins 3, 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 3, a member of class 3 synaptotagmins, is located in the brain and localized to the active zone and plasma membrane. It functions as a Ca2+ sensor for fast exocytosis. It, along with synaptotagmins 5,6, and 10, has disulfide bonds at its N-terminus. 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 second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 176048 [Multi-domain] Cd Length: 134 Bit Score: 54.82 E-value: 7.63e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 118 GEIHLRLEVVPgvHASRLRCAVLEARDLAPKDRNGASDPFVRVHY--NGR---TQETSVVKKSCYPRWNET--FDFELEK 190
Cdd:cd08403   1 GELMFSLCYLP--TAGRLTLTIIKARNLKAMDITGFSDPYVKVSLmcEGRrlkKKKTSVKKNTLNPTYNEAlvFDVPPEN 78

                        90       100
                ....*....|....*....|....*..
gi 84993718 191 GASEALLVEAWDWDLVSRNDFLGKVAV 217
Cdd:cd08403  79 VDNVSLIIAVVDYDRVGHNELIGVCRV 105

C2 domain present in the putative elicitor-responsive gene; In plants elicitor-responsive proteins are triggered in response to specific elicitor molecules such as glycolproteins, peptides, carbohydrates and lipids. A host of defensive responses are also triggered resulting in localized cell death. Antimicrobial secondary metabolites, such as phytoalexins, or defense-related proteins, including pathogenesis-related (PR) proteins are also produced. There is a single C2 domain present here. 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 have a type-II topology.

Pssm-ID: 176014 [Multi-domain] Cd Length: 124 Bit Score: 54.26 E-value: 8.07e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 140 LEARDLAPKDRNGASDPFVRVHYNGRTQETSVVK-KSCYPRWNETFDFELEKGASEA---LLVEAWDWDLVSRNDFLGKV 215
Cdd:cd04049   8 ISAKGLQDTDFLGKIDPYVIIQCRTQERKSKVAKgDGRNPEWNEKFKFTVEYPGWGGdtkLILRIMDKDNFSDDDFIGEA 87

                        90       100
                ....*....|....*....|.
gi 84993718 216 AVNVQRLCSAQQEEGWFRLQP 236
Cdd:cd04049  88 TIHLKGLFEEGVEPGTAELVP 108

C2 domain second repeat in Copine; There are 2 copies of the C2 domain present in copine, a protein involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth. 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.

Pssm-ID: 176012 [Multi-domain] Cd Length: 110 Bit Score: 53.72 E-value: 9.09e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 140 LEARDLAPKDRNGASDPFV---RVHYNGRTQ---ETSVVKKSCYPRWNEtFDFELEK----GASEALLVEAWDWDLVSRN 209
Cdd:cd04047   7 FSGKKLDKKDFFGKSDPFLeisRQSEDGTWVlvyRTEVIKNTLNPVWKP-FTIPLQKlcngDYDRPIKIEVYDYDSSGKH 85

                        90       100
                ....*....|....*....|
gi 84993718 210 DFLGKVAVNVQRLCSAQQEE 229
Cdd:cd04047  86 DLIGEFETTLDELLKSSPLE 105

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.

Pssm-ID: 175975 [Multi-domain] Cd Length: 134 Bit Score: 54.51 E-value: 9.19e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYciVKVD---NEPII---RTATVWKTLCPFWGEDYQVHLPPTFH---TVAFYVMDEDA 77
Cdd:cd00276  16 LTVVVLKARNLPPSDGKGLSDPY--VKVSllqGGKKLkkkKTSVKKGTLNPVFNEAFSFDVPAEQLeevSLVITVVDKDS 93

                        90
                ....*....|....*.
gi 84993718  78 LSRDDVIGKVCLTRDA 93
Cdd:cd00276  94 VGRNEVIGQVVLGPDS 109

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

Pssm-ID: 176000 [Multi-domain] Cd Length: 123 Bit Score: 53.83 E-value: 1.04e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   2 AKRSSLSIRIVEGKNLPAKDITGSSDPYCivKVDNEPI------IRTATVWKTLCPFWGEDYqvhlppTFH--------- 66
Cdd:cd04035  12 PANSALHCTIIRAKGLKAMDANGLSDPYV--KLNLLPGaskatkLRTKTVHKTRNPEFNETL------TYYgiteediqr 83

                        90       100
                ....*....|....*....|....*...
gi 84993718  67 -TVAFYVMDEDALsRDDVIG--KVCLTR 91
Cdd:cd04035  84 kTLRLLVLDEDRF-GNDFLGetRIPLKK 110

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

Pssm-ID: 227371 [Multi-domain] Cd Length: 1227 Bit Score: 59.00 E-value: 1.05e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718    6 SLSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHLPP-TFHTVAFYVMDEDALSRDDVI 84
Cdd:COG5038 1041 YLTIMLRSGENLPSSDENGYSDPFVKLFLNEKSVYKTKVVKKTLNPVWNEEFTIEVLNrVKDVLTINVNDWDSGEKNDLL 1120


                 ..
gi 84993718   85 GK 86
Cdd:COG5038 1121 GT 1122

C2 domain third repeat in Ferlin; Ferlins are involved in vesicle fusion events. Ferlins and other proteins, such as Synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1). Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

Pssm-ID: 175985 [Multi-domain] Cd Length: 151 Bit Score: 53.79 E-value: 1.97e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 148 KDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDF-ELEKGASEALLVEAWDWDLVSRNDFLGKVAVNVQRLcSAQ 226
Cdd:cd04018  29 GEKKELVDPYVEVSFAGQKVKTSVKKNSYNPEWNEQIVFpEMFPPLCERIKIQIRDWDRVGNDDVIGTHFIDLSKI-SNS 107

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 84993718 227 QEEGW-----------------FRLQPDQSKSRQGKG 246
Cdd:cd04018 108 GDEGFlptfgpsfvnlygspreYSLLDDHQDLNEGLG 144

C2 domain present in Phosphatidylserine decarboxylase (PSD); PSD is involved in the biosynthesis of aminophospholipid by converting phosphatidylserine (PtdSer) to phosphatidylethanolamine (PtdEtn). There is a single C2 domain present and it is thought to confer PtdSer binding motif that is common to PKC and synaptotagmin. 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.

Pssm-ID: 176004 [Multi-domain] Cd Length: 108 Bit Score: 52.26 E-value: 3.05e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLaPKDRNGAS-----DPFVRVHYNGRTQETSVVKKSCYPRWNETFDFEL---EKGASEALLVeaWDWDLVSRND 210
Cdd:cd04039   7 IKSITDL-PPLKNMTRtgfdmDPFVIISFGRRVFRTSWRRHTLNPVFNERLAFEVyphEKNFDIQFKV--LDKDKFSFND 83

                        90       100
                ....*....|....*....|..
gi 84993718 211 FLGKVAVNVQRL-CSAQQEEGW 231
Cdd:cd04039  84 YVATGSLSVQELlNAAPQPDPE 105

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.

Pssm-ID: 176034 [Multi-domain] Cd Length: 128 Bit Score: 52.35 E-value: 4.19e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   4 RSSLSIRIVEGKNLPAKDI-TGSSDPYciVKV----DNEPIIRTATVWKTLCPFWGEDYQVH-LPPT---FHTVAFYVMD 74
Cdd:cd08388  15 KKALLVNIIECRDLPAMDEqSGTSDPY--VKLqllpEKEHKVKTRVLRKTRNPVYDETFTFYgIPYNqlqDLSLHFAVLS 92

                        90
                ....*....|....*.
gi 84993718  75 EDALSRDDVIGKVCLT 90
Cdd:cd08388  93 FDRYSRDDVIGEVVCP 108

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.

Pssm-ID: 176036 [Multi-domain] Cd Length: 123 Bit Score: 51.87 E-value: 5.13e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 134 RLRCAVLEARDLAPKDRNGA-SDPFVRVHY---NGRTQETSVVKKSCYPRWNETFDFELEkgASEA----LLVEAWDWDL 205
Cdd:cd08390  15 QLTVSLIKARNLPPRTKDVAhCDPFVKVCLlpdERRSLQSKVKRKTQNPNFDETFVFQVS--FKELqrrtLRLSVYDVDR 92

                        90       100       110
                ....*....|....*....|....*....|.
gi 84993718 206 VSRNDFLGKVAVNVQRLCSAQQEEGWFRLQP 236
Cdd:cd08390  93 FSRHCIIGHVLFPLKDLDLVKGGVVWRDLEP 123

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.

Pssm-ID: 176033 [Multi-domain] Cd Length: 124 Bit Score: 52.02 E-value: 5.93e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 118 GEIHLRLEVVP--GVhasrLRCAVLEARDLAPKDRNGASDPFVRVHY---NGRTQETSVVKKSCYPRWNETFDFELEKG- 191
Cdd:cd08387   3 GELHFSLEYDKdmGI----LNVKLIQARNLQPRDFSGTADPYCKVRLlpdRSNTKQSKIHKKTLNPEFDESFVFEVPPQe 78

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 84993718 192 -ASEALLVEAWDWDLVSRNDFLGKVAVNVQRLCSAQQEEGWFRLQP 236
Cdd:cd08387  79 lPKRTLEVLLYDFDQFSRDECIGVVELPLAEVDLSEKLDLWRKIQS 124

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

Pssm-ID: 176060 [Multi-domain] Cd Length: 126 Bit Score: 51.98 E-value: 6.00e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 152 GASDPFVRVHYNGRTQ--ETSVVKKSCYPRWNETFDFELeKGASEALLVEAWDWDLVSRNDFLGKVAVNVQRLC---SAQ 226
Cdd:cd08678  16 GSSNPYCVLEMDEPPQkyQSSTQKNTSNPFWDEHFLFEL-SPNSKELLFEVYDNGKKSDSKFLGLAIVPFDELRknpSGR 94

                        90       100
                ....*....|....*....|..
gi 84993718 227 QEegwFRLQPDQSKSRQGKGNL 248
Cdd:cd08678  95 QI---FPLQGRPYEGDSVSGSI 113

C2 domain first repeat present in RasA1 and RasA4; Rasal1 and RasA4 are both members of GAP1 (GTPase activating protein 1). Rasal1 responds to repetitive Ca2+ signals by associating with the plasma membrane and deactivating Ras. RasA4 suppresses 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. Both of these proteins contains two C2 domains, a Ras-GAP domain, a plextrin homology (PH)-like domain, and a Bruton's Tyrosine Kinase (BTK) zinc binding 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. This cd contains the first C2 repeat, C2A, and has a type-I topology.

Pssm-ID: 176018 [Multi-domain] Cd Length: 121 Bit Score: 49.44 E-value: 3.99e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNGASDPFVRVHY-NGRTQETSVVKKSCYPRWNETFDFELEKGAsEALLVEAWDWDLVSRNDFLG 213
Cdd:cd04054   2 LYIRIVEGKNLPAKDITGSSDPYCIVKVdNEVIIRTATVWKTLNPFWGEEYTVHLPPGF-HTVSFYVLDEDTLSRDDVIG 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 84993718 214 KVAVNVQRLCSAQQE-EGWFRLQP-DQSKSRQGKgnlgsLQLEVRL 257
Cdd:cd04054  81 KVSLTREVISAHPRGiDGWMNLTEvDPDEEVQGE-----IHLELSV 121

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

Pssm-ID: 175981 [Multi-domain] Cd Length: 132 Bit Score: 49.58 E-value: 4.12e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   6 SLSIRIVEGKNL-P---AKDITGSS------DPYCIVKVDNEPIIRTATVWKTLCPFWGEDY--QVHlppTFHTVAFYVM 73
Cdd:cd04014   5 TLKIKICEAVDLkPtdwSTRHAVPKkgsqllDPYVSIDVDDTHIGKTSTKPKTNSPVWNEEFttEVH---NGRNLELTVF 81

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 84993718  74 DEDALSRDDVIGKVCLT-RDALASHPKGFSGWTHLvevdpneEVQGEIHLRLE 125
Cdd:cd04014  82 HDAAIGPDDFVANCTISfEDLIQRGSGSFDLWVDL-------EPQGKLHVKIE 127

C2 domain second repeat present in Synaptotagmin 15; 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. 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.

Pssm-ID: 176054 [Multi-domain] Cd Length: 137 Bit Score: 49.26 E-value: 5.69e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 118 GEIHLRLEVVPGVHasRLRCAVLEARDLAPKDRNGAsDPFVRV---HYNG--RTQETSVVKKSCYPRWNETFDFEL-EKG 191
Cdd:cd08409   2 GDIQISLTYNPTLN--RLTVVVLRARGLRQLDHAHT-SVYVKVslmIHNKvvKTKKTEVVDGAASPSFNESFSFKVtSRQ 78

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 84993718 192 ASEA-LLVEAWDWDLVSRNDFLGKVAVNVQRLCSAQQEEGW 231
Cdd:cd08409  79 LDTAsLSLSVMQSGGVRKSKLLGRVVLGPFMYARGKELEHW 119

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

Pssm-ID: 176006 [Multi-domain] Cd Length: 111 Bit Score: 48.41 E-value: 6.64e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 142 ARDLAPKDRN-GASDPFVRVHYNG------RTQetsVVKKSCYPRWNETFdFEL----EKGASEALLVEAWDWDLVSRND 210
Cdd:cd04041  10 ATDLPKADFGtGSSDPYVTASFAKfgkplySTR---IIRKDLNPVWEETW-FVLvtpdEVKAGERLSCRLWDSDRFTADD 85

                        90       100
                ....*....|....*....|....*...
gi 84993718 211 FLGKVAVNVQRLcsaQQEEGW--FRLQP 236
Cdd:cd04041  86 RLGRVEIDLKEL---IEDRNWmgRREDG 110

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

Pssm-ID: 175993 [Multi-domain] Cd Length: 127 Bit Score: 47.95 E-value: 1.46e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVdNEPIIRTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDalsrDDVIGK 86
Cdd:cd04027   3 ISITVVCAQGLIAKDKTGTSDPYVTVQV-GKTKKRTKTIPQNLNPVWNEKFHFECHNSSDRIKVRVWDED----DDIKSR 77

                        90       100
                ....*....|....*....|....
gi 84993718  87 VcltRDALASHPKGFSGWThLVEV 110
Cdd:cd04027  78 L---KQKFTRESDDFLGQT-IIEV 97

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

Pssm-ID: 176024 [Multi-domain] Cd Length: 121 Bit Score: 47.31 E-value: 1.85e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLapkdRNGASDPFVRV---HYNGRTQEtsvVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVSrNDFLGKV 215
Cdd:cd08378   6 VVKARGL----PANSNDPVVEVklgNYKGSTKA---IERTSNPEWNQVFAFSKDRLQGSTLEVSVWDKDKAK-DDFLGGV 77


                ....*
gi 84993718 216 AVNVQ 220
Cdd:cd08378  78 CFDLS 82

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.

Pssm-ID: 176030 [Multi-domain] Cd Length: 133 Bit Score: 47.73 E-value: 1.89e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   3 KRSSLSIRIVEGKNLPAKDITGSSDPYciVKVDNEPII------RTATVWKTLCPFWGEDYQVHLPPT---FHTVAFYVM 73
Cdd:cd08384  11 QRRGLIVGIIRCVNLAAMDANGYSDPF--VKLYLKPDAgkkskhKTQVKKKTLNPEFNEEFFYDIKHSdlaKKTLEITVW 88

                        90       100
                ....*....|....*....|
gi 84993718  74 DEDALSRDDVIGKVCLTRDA 93
Cdd:cd08384  89 DKDIGKSNDYIGGLQLGINA 108

C2 domain present in cytosolic PhosphoLipase A2 (cPLA2); A single copy of the C2 domain is present in cPLA2 which releases arachidonic acid from membranes initiating the biosynthesis of potent inflammatory mediators such as prostaglandins, leukotrienes, and platelet-activating factor. 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 of this cd have a type-II topology.

Pssm-ID: 176001 [Multi-domain] Cd Length: 119 Bit Score: 46.87 E-value: 2.62e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 134 RLRCAVLEARDLAPKDRNGASDPFVRVHY----NGRTQeTSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDLVsRN 209
Cdd:cd04036   1 LLTVRVLRATNITKGDLLSTPDCYVELWLptasDEKKR-TKTIKNSINPVWNETFEFRIQSQVKNVLELTVMDEDYV-MD 78

                        90       100
                ....*....|....*....|....*..
gi 84993718 210 DFLGKVAVNVQRLCSAQQEEGWFRLQP 236
Cdd:cd04036  79 DHLGTVLFDVSKLKLGEKVRVTFSLNP 105

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

Pssm-ID: 176028 [Multi-domain] Cd Length: 123 Bit Score: 46.92 E-value: 3.15e-06

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   6 SLSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHLPPTfHTVAFYVMDE 75
Cdd:cd08382   1 KVRLTVLCADGLAKRDLFRLPDPFAVITVDGGQTHSTDVAKKTLDPKWNEHFDLTVGPS-SIITIQVFDQ 69

C2 domain second repeat in Ferlin; Ferlins are involved in vesicle fusion events. Ferlins and other proteins, such as Synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1). Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.

Pssm-ID: 175978 [Multi-domain] Cd Length: 111 Bit Score: 46.03 E-value: 4.33e-06

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 84993718 139 VLEARDLApkdrNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFE 187
Cdd:cd04011  10 VIEARQLV----GGNIDPVVKVEVGGQKKYTSVKKGTNCPFYNEYFFFN 54

C2 domain present in E3 ubiquitin ligase; E3 ubiquitin ligase is part of the ubiquitylation mechanism responsible for controlling surface expression of membrane proteins. The sequential action of several enzymes are involved: ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, and ubiquitin-protein ligase E3 which is responsible for substrate recognition and promoting the transfer of ubiquitin to the target protein. E3 ubiquitin ligase is composed of an N-terminal C2 domain, 4 WW domains, and a HECTc 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.

Pssm-ID: 175988 [Multi-domain] Cd Length: 125 Bit Score: 46.12 E-value: 5.71e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   4 RSSLSIRIVEGKnLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHLPPtFHTVAFYVMDEDALSRDDV 83
Cdd:cd04021   1 KSQLQITVESAK-LKSNSKSFKPDPYVEVTVDGQPPKKTEVSKKTSNPKWNEHFTVLVTP-QSTLEFKVWSHHTLKADVL 78

                        90
                ....*....|....*
gi 84993718  84 IGKVCLT-RDALASH 97
Cdd:cd04021  79 LGEASLDlSDILKNH 93

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.

Pssm-ID: 175989 [Multi-domain] Cd Length: 127 Bit Score: 46.18 E-value: 6.80e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNEpIIRTATVWKTLCPFWGE--DYQVHLPPTFHT--VAFYVMDEDALSR-D 81
Cdd:cd04022   2 LVVEVVDAQDLMPKDGQGSSSAYVELDFDGQ-KKRTRTKPKDLNPVWNEklVFNVSDPSRLSNlvLEVYVYNDRRSGRrR 80

                        90
                ....*....|....*.
gi 84993718  82 DVIGKVCLTRDALASH 97
Cdd:cd04022  81 SFLGRVRISGTSFVPP 96

C2 domain second repeat in Ferlin; Ferlins are involved in vesicle fusion events. Ferlins and other proteins, such as Synaptotagmins, are implicated in facilitating the fusion process when cell membranes fuse together. There are six known human Ferlins: Dysferlin (Fer1L1), Otoferlin (Fer1L2), Myoferlin (Fer1L3), Fer1L4, Fer1L5, and Fer1L6. Defects in these genes can lead to a wide range of diseases including muscular dystrophy (dysferlin), deafness (otoferlin), and infertility (fer-1, fertilization factor-1). Structurally they have 6 tandem C2 domains, designated as (C2A-C2F) and a single C-terminal transmembrane domain, though there is a new study that disputes this and claims that there are actually 7 tandem C2 domains with another C2 domain inserted between C2D and C2E. In a subset of them (Dysferlin, Myoferlin, and Fer1) there is an additional conserved domain called DysF. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.

Pssm-ID: 175978 [Multi-domain] Cd Length: 111 Bit Score: 45.26 E-value: 9.32e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   8 SIRIVEGKNLPakdiTGSSDPYCIVKVDNEPIiRTATVWKTLCPFWGED--YQVHLPPT--FHT-VAFYVMDEDALSRDD 82
Cdd:cd04011   7 RVRVIEARQLV----GGNIDPVVKVEVGGQKK-YTSVKKGTNCPFYNEYffFNFHESPDelFDKiIKISVYDSRSLRSDT 81


                ...
gi 84993718  83 VIG 85
Cdd:cd04011  82 LIG 84

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

Pssm-ID: 176015 [Multi-domain] Cd Length: 105 Bit Score: 44.86 E-value: 1.03e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 142 ARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKGASEALLVEAWDWDlvsRNDFLGKVAVNVQR 221
Cdd:cd04050   9 AKNLPLAKSTKEPSPYVELTVGKTTQKSKVKERTNNPVWEEGFTFLVRNPENQELEIEVKDDK---TGKSLGSLTLPLSE 85

                        90       100
                ....*....|....*....|
gi 84993718 222 LCSAQQE--EGWFRLQPDQS 239
Cdd:cd04050  86 LLKEPDLtlDQPFPLDNSGP 105

C2 domain found in fungal Ingression 1 (Inn1) proteins; Saccharomyces cerevisiae Inn1 associates with the contractile actomyosin ring at the end of mitosis and is needed for cytokinesis. The C2 domain of Inn1, located at the N-terminus, is required for ingression of the plasma membrane. The C-terminus is relatively unstructured and contains eight PXXP motifs that are thought to mediate interaction of Inn1 with other proteins with SH3 domains in the cytokinesis proteins Hof1 (an F-BAR protein) and Cyk3 (whose overexpression can restore primary septum formation in Inn1Delta cells) as well as recruiting Inn1 to the bud-neck by binding to Cyk3. Inn1 and Cyk3 appear to cooperate in activating chitin synthase Chs2 for primary septum formation, which allows coordination of actomyosin ring contraction with ingression of the cleavage furrow. It is thought that the C2 domain of Inn1 helps to preserve the link between the actomyosin ring and the plasma membrane, contributing both to membrane ingression, as well as to stability of the contracting ring. Additionally, Inn1 might induce curvature of the plasma membrane adjacent to the contracting ring, thereby promoting ingression of the membrane. It has been shown that the C2 domain of human synaptotagmin induces curvature in target membranes and thereby contributes to fusion of these membranes with synaptic vesicles. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176063 [Multi-domain] Cd Length: 118 Bit Score: 45.32 E-value: 1.06e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSC-YPRWNETFDFELEKGASEALLVEAWDWDLvSRNDFLG 213
Cdd:cd08681   3 LVVVVLKARNLPNKRKLDKQDPYCVLRIGGVTKKTKTDFRGGqHPEWDEELRFEITEDKKPILKVAVFDDDK-RKPDLIG 81

                        90       100
                ....*....|....*....|..
gi 84993718 214 KVAVNVQRLCSAQQEEGWFRLQ 235
Cdd:cd08681  82 DTEVDLSPALKEGEFDDWYELT 103

C2 domain second repeat present in Synaptotagmin 4; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 4, a member of class 4 synaptotagmins, is located in the brain. It functions are unknown. It, like synaptotagmin-11, has an Asp to Ser substitution in its C2A domain. 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.

Pssm-ID: 176049 [Multi-domain] Cd Length: 136 Bit Score: 45.50 E-value: 1.32e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYciVKV----DNEPIIRTATVWK--TLCPFWGEDYQVHLPPTFH---TVAFYVMDEDA 77
Cdd:cd08404  17 LTVVVLKARHLPKMDVSGLADPY--VKVnlyyGKKRISKKKTHVKkcTLNPVFNESFVFDIPSEELediSVEFLVLDSDR 94

                        90
                ....*....|..
gi 84993718  78 LSRDDVIGKVCL 89
Cdd:cd08404  95 VTKNEVIGRLVL 106

C2 domain first repeat in Copine; There are 2 copies of the C2 domain present in copine, a protein involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth. 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.

Pssm-ID: 176013 [Multi-domain] Cd Length: 120 Bit Score: 44.48 E-value: 2.00e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718  11 IVEGKNLPAKDITGSSDPYCIVKVDNEP------IIRTATVWKTLCPFWGEdyQVHLPPTFHTVA---FYVMDED----A 77
Cdd:cd04048   6 SISCRNLLDKDVLSKSDPFVVVYVKTGGsgqwveIGRTEVIKNNLNPDFVT--TFTVDYYFEEVQklrFEVYDVDskskD 83

                        90       100
                ....*....|....*....|..
gi 84993718  78 LSRDDVIGKVCLTRDALASHPK 99
Cdd:cd04048  84 LSDHDFLGEAECTLGEIVSSPG 105

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

Pssm-ID: 175984 [Multi-domain] Cd Length: 135 Bit Score: 44.46 E-value: 2.87e-05

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 84993718  14 GKNLPAKDITGSSDPYCIVKVDNEpIIRTATVWKTLCPFW 53
Cdd:cd04017  10 ARDLLAADKSGLSDPFARVSFLNQ-SQETEVIKETLSPTW 48

Bruton's tyrosine kinase Cys-rich motif; Zinc-binding motif containing conserved cysteines and a histidine. Always found C-terminal to PH domains (but not all PH domains are followed by BTK motifs). The crystal structure shows this motif packs against the PH domain. The PH+Btk module pair has been called the Tec homology (TH) region.

Pssm-ID: 128417 Cd Length: 36 Bit Score: 41.60 E-value: 2.94e-05

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 84993718    628 NRGLLRSYHPGIFRGDKWSCCHQKDKTDQGCDKTH 662
Cdd:smart00107   1 NNNLLQKYHPSFWVDGKWLCCQQSEKNAPGCTPYE 35

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

Pssm-ID: 175986 [Multi-domain] Cd Length: 150 Bit Score: 43.81 E-value: 6.94e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 84993718 135 LRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVK-KSCYPRWNETFDF 186
Cdd:cd04019   2 LRVTVIEAQDLVPSDKNRVPEVFVKAQLGNQVLRTRPSQtRNGNPSWNEELMF 54

C2 domain fourth repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); plant subset; MCTPs are involved in Ca2+ signaling at the membrane. Plant-MCTPs are composed of a variable N-terminal sequence, four C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the fourth C2 repeat, C2D, and has a type-II topology.

Pssm-ID: 176025 [Multi-domain] Cd Length: 126 Bit Score: 42.39 E-value: 1.23e-04

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 84993718  17 LPAKDITGSSDPYCIVKVDNEpIIRTATVWKTLCPFWGEDY--QVHLPPTFHTVAFY---VMDEDALSRDDV-IGKV 87
Cdd:cd08379  15 LRAKDGRGSTDAYCVAKYGPK-WVRTRTVEDSSNPRWNEQYtwPVYDPCTVLTVGVFdnsQSHWKEAVQPDVlIGKV 90

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

Pssm-ID: 227371 [Multi-domain] Cd Length: 1227 Bit Score: 45.14 E-value: 2.02e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718  139 VLEARDLAPKDR--NGASDPFVRVHYNGRTQ-ETSVVKKSCYPRWNETFDFELEKgASEALLVEAWDWDLVSRNDFLGKV 215
Cdd:COG5038  442 IKSAEGLKKSDStiNGTVDPYITVTFSDRVIgKTRVKKNTLNPVWNETFYILLNS-FTDPLNLSLYDFNSFKSDKVVGST 520


                 ....*..
gi 84993718  216 AVNVQRL 222
Cdd:COG5038  521 QLDLALL 527

Pleckstrin homology domain containing, family J member 1 Pleckstrin homology (PH) domain; PLEKHJ1 (also called GNRPX2/Guanine nucleotide-releasing protein x ). It contains a single PH domain. Very little information is known about PLEKHJ1. PLEKHJ1 has been shown to interact with IKBKG (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma) and KRT33B (keratin 33B). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270078 Cd Length: 123 Bit Score: 41.54 E-value: 2.08e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 504 EKEELDLqralnSQAPPVKEGPlfIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKST----FIKLASIRAA-EK 578
Cdd:cd13258   5 EKELAAL-----SSQPAEKEGK--IAERQMGGPKKSEVFKERWFKLKGNLLFYFRTNEFGDCSepigAIVLENCRVQmEE 77

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 84993718 579 VEEKSFGSShimqVIYADDVGRAQtvYLQCKCVNELNQWLSALRKAS 625
Cdd:cd13258  78 ITEKPFAFS----IVFNDEPEKKY--IFSCRSEEQCEQWIEALRQAS 118

C2 domain present in Ras GTPase activating protein (GAP) family; SynGAP, GAP1, RasGAP, and neurofibromin are all members of the Ras-specific GAP (GTPase-activating protein) family. SynGAP regulates the MAP kinase signaling pathway and is critical for cognition and synapse function. Mutations in this gene causes mental retardation in humans. SynGAP contains a PH-like domain, a C2 domain, and a Ras-GAP 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.

Pssm-ID: 175980 [Multi-domain] Cd Length: 146 Bit Score: 42.29 E-value: 2.08e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNgasdpFVRVHYNG----RTqeTSVVK-KSCYprWNETFDF-ELEkgASEALLVEAW-DWDLVS 207
Cdd:cd04013  13 LKLWIIEAKGLPPKKRY-----YCELCLDKtlyaRT--TSKLKtDTLF--WGEHFEFsNLP--PVSVITVNLYrESDKKK 81

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 84993718 208 R---NDFLGKVAVNVQRLCSAQQEEGWFRLQPD----QSKSRQGKGNLGSLQLEVRLRDETVLP 264
Cdd:cd04013  82 KkdkSQLIGTVNIPVTDVSSRQFVEKWYPVSTPkgngKSGGKEGKGESPSIRIKARYQSTRVLP 145

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

Pssm-ID: 176060 [Multi-domain] Cd Length: 126 Bit Score: 41.58 E-value: 2.20e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718  23 TGSSDPYCIVKVDnEPI--IRTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDALSRDDVIGKVCLTRDALASHPKG 100
Cdd:cd08678  15 AGSSNPYCVLEMD-EPPqkYQSSTQKNTSNPFWDEHFLFELSPNSKELLFEVYDNGKKSDSKFLGLAIVPFDELRKNPSG 93

C2 domain second repeat present in Synaptotagmins 3, 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 3, a member of class 3 synaptotagmins, is located in the brain and localized to the active zone and plasma membrane. It functions as a Ca2+ sensor for fast exocytosis. It, along with synaptotagmins 5,6, and 10, has disulfide bonds at its N-terminus. 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 second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 176048 [Multi-domain] Cd Length: 134 Bit Score: 41.72 E-value: 2.44e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYciVKV----DNEPIIRTATVWK--TLCPFWGEDYQVHLPPTFH---TVAFYVMDEDA 77
Cdd:cd08403  16 LTLTIIKARNLKAMDITGFSDPY--VKVslmcEGRRLKKKKTSVKknTLNPTYNEALVFDVPPENVdnvSLIIAVVDYDR 93

                        90
                ....*....|.
gi 84993718  78 LSRDDVIGkVC 88
Cdd:cd08403  94 VGHNELIG-VC 103

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.

Pssm-ID: 176067 [Multi-domain] Cd Length: 119 Bit Score: 41.29 E-value: 2.46e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 122 LRLEVVpgVHASRLRCAVLEARDLaPKDRNGASDPFVRVHY-----NGRTQETSVVKKSCYPRWNETFDFELEKGAS-EA 195
Cdd:cd08685   3 LKLSIE--GQNRKLTLHVLEAKGL-RSTNSGTCNSYVKISLspdkeVRFRQKTSTVPDSANPLFHETFSFDVNERDYqKR 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 84993718 196 LLVEAWDWDLVSRND-FLGKVAVNVQRLCSAQQEEGWFRL 234
Cdd:cd08685  80 LLVTVWNKLSKSRDSgLLGCMSFGVKSIVNQKEISGWYYL 119

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

Pssm-ID: 176064 [Multi-domain] Cd Length: 126 Bit Score: 41.28 E-value: 2.80e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   8 SIRIVEGKNLPAKDITGSSDPYCIVKVDNEpIIRTATVWKTLCPFWGEDYQVHLP------PTFHTVAFYVMDEDALSRD 81
Cdd:cd08682   2 QVTVLQARGLLCKGKSGTNDAYVIIQLGKE-KYSTSVKEKTTSPVWKEECSFELPgllsgnGNRATLQLTVMHRNLLGLD 80

                        90
                ....*....|...
gi 84993718  82 DVIGKVCLTRDAL 94
Cdd:cd08682  81 KFLGQVSIPLNDL 93

C2 domain second repeat in Copine; There are 2 copies of the C2 domain present in copine, a protein involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth. 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.

Pssm-ID: 176012 [Multi-domain] Cd Length: 110 Bit Score: 40.63 E-value: 3.56e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718  12 VEGKNLPAKDITGSSDPYCIV-KVDNE----PIIRTATVWKTLCPFW-----------GEDYQVHLpptfhtvAFYVMDE 75
Cdd:cd04047   7 FSGKKLDKKDFFGKSDPFLEIsRQSEDgtwvLVYRTEVIKNTLNPVWkpftiplqklcNGDYDRPI-------KIEVYDY 79

                        90       100
                ....*....|....*....|.
gi 84993718  76 DALSRDDVIGKVCLTRDALAS 96
Cdd:cd04047  80 DSSGKHDLIGEFETTLDELLK 100

C2 domain present in cytosolic PhosphoLipase A2 (cPLA2); A single copy of the C2 domain is present in cPLA2 which releases arachidonic acid from membranes initiating the biosynthesis of potent inflammatory mediators such as prostaglandins, leukotrienes, and platelet-activating factor. 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 of this cd have a type-II topology.

Pssm-ID: 176001 [Multi-domain] Cd Length: 119 Bit Score: 40.71 E-value: 4.09e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNEP--IIRTATVWKTLCPFWGEDYQVHLPPTFHTVA-FYVMDEDALsRDDV 83
Cdd:cd04036   2 LTVRVLRATNITKGDLLSTPDCYVELWLPTASdeKKRTKTIKNSINPVWNETFEFRIQSQVKNVLeLTVMDEDYV-MDDH 80


                ....
gi 84993718  84 IGKV 87
Cdd:cd04036  81 LGTV 84

C2 domain present in Calpain proteins; A single C2 domain is found in calpains (EC 3.4.22.52, EC 3.4.22.53), calcium-dependent, non-lysosomal cysteine proteases. Caplains are classified as belonging to Clan CA by MEROPS and include six families: C1, C2, C10, C12, C28, and C47. 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.

Pssm-ID: 176011 [Multi-domain] Cd Length: 126 Bit Score: 40.72 E-value: 4.92e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCYPRWNETFDFELEKgASEALLVEAWDWDLVSRnDFLGKVAVN 218
Cdd:cd04046   9 VHSAEGLSKQDSGGGADPYVIIKCEGESVRSPVQKDTLSPEFDTQAIFYRKK-PRSPIKIQVWNSNLLCD-EFLGQATLS 86

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 84993718 219 VQRLCSAQQEEgwfrLQPDQSKSRQGKGNLGSLQLEV 255
Cdd:cd04046  87 ADPNDSQTLRT----LPLRKRGRDAAGEVPGTISVKV 119

C2 domain present in Intersectin; A single instance of the C2 domain is located C terminally in the intersectin protein. Intersectin functions as a scaffolding protein, providing a link between the actin cytoskeleton and the components of endocytosis and plays a role in signal transduction. In addition to C2, intersectin contains several additional domains including: Eps15 homology domains, SH3 domains, a RhoGEF domain, and a PH 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. The members here have topology I.

Pssm-ID: 176021 [Multi-domain] Cd Length: 136 Bit Score: 40.83 E-value: 5.38e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPiIRTATVWKTLCPFWGEDYQVHLPPTFHTV-AFYVMDEDALSRDDVIG 85
Cdd:cd08375  17 LMVVIVEGRDLKPCNSNGKSDPYCEVSMGSQE-HKTKVVSDTLNPKWNSSMQFFVKDLEQDVlCITVFDRDFFSPDDFLG 95

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 84993718  86 KVCLTRDALASHPKGFSG-WTH---LVEVDpneevQGEIHLRLE 125
Cdd:cd08375  96 RTEIRVADILKETKESKGpITKrllLHEVP-----TGEVVVKLD 134

C2 domain found in fungal Ingression 1 (Inn1) proteins; Saccharomyces cerevisiae Inn1 associates with the contractile actomyosin ring at the end of mitosis and is needed for cytokinesis. The C2 domain of Inn1, located at the N-terminus, is required for ingression of the plasma membrane. The C-terminus is relatively unstructured and contains eight PXXP motifs that are thought to mediate interaction of Inn1 with other proteins with SH3 domains in the cytokinesis proteins Hof1 (an F-BAR protein) and Cyk3 (whose overexpression can restore primary septum formation in Inn1Delta cells) as well as recruiting Inn1 to the bud-neck by binding to Cyk3. Inn1 and Cyk3 appear to cooperate in activating chitin synthase Chs2 for primary septum formation, which allows coordination of actomyosin ring contraction with ingression of the cleavage furrow. It is thought that the C2 domain of Inn1 helps to preserve the link between the actomyosin ring and the plasma membrane, contributing both to membrane ingression, as well as to stability of the contracting ring. Additionally, Inn1 might induce curvature of the plasma membrane adjacent to the contracting ring, thereby promoting ingression of the membrane. It has been shown that the C2 domain of human synaptotagmin induces curvature in target membranes and thereby contributes to fusion of these membranes with synaptic vesicles. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176063 [Multi-domain] Cd Length: 118 Bit Score: 40.31 E-value: 6.32e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNE-----PIIRTATVwktlcPFWgeDYQVH---LPPTFHTVAFYVMDEDAl 78
Cdd:cd08681   3 LVVVVLKARNLPNKRKLDKQDPYCVLRIGGVtkktkTDFRGGQH-----PEW--DEELRfeiTEDKKPILKVAVFDDDK- 74

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 84993718  79 SRDDVIGKVCLT-RDALasHPKGFSGWthlVEVDPNEEVQGEIHLRL 124
Cdd:cd08681  75 RKPDLIGDTEVDlSPAL--KEGEFDDW---YELTLKGRYAGEVYLEL 116

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+.

Pssm-ID: 175997 [Multi-domain] Cd Length: 125 Bit Score: 40.31 E-value: 6.39e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   2 AKRSSLSIRIVEGKNLPAKDITGSSDPYciVKV------DNEPIIRTATVWKTLCPFWGE--DYQVHLPPTF--HTVAFY 71
Cdd:cd04031  13 KVTSQLIVTVLQARDLPPRDDGSLRNPY--VKVyllpdrSEKSKRRTKTVKKTLNPEWNQtfEYSNVRRETLkeRTLEVT 90

                        90
                ....*....|....*.
gi 84993718  72 VMDEDALSRDDVIGKV 87
Cdd:cd04031  91 VWDYDRDGENDFLGEV 106

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

Pssm-ID: 176020 Cd Length: 133 Bit Score: 40.34 E-value: 6.59e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRN----GASDPFVR--------------VHYNGRTQETSVVKKSCYP------------RWNETF 184
Cdd:cd08374   2 LRVIVWNTRDVLNDDTNitgeKMSDIYVKgwldgleedkqktdVHYRSLDGEGNFNWRFVFPfdylpaekkivvIKKEHF 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 84993718 185 DfelEKGASE-----ALLVEAWDWDLVSRNDFLGKVAVNVQRL 222
Cdd:cd08374  82 W---SLDETEykippKLTLQVWDNDKFSPDDFLGSLELDLSIL 121

C2 domain present in Phosphoinositide-specific phospholipases C (PLC); PLCs are involved in the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) to d-myo-inositol-1,4,5-trisphosphate (1,4,5-IP3) and sn-1,2-diacylglycerol (DAG). 1,4,5-IP3 and DAG are second messengers in eukaryotic signal transduction cascades. PLC is composed of a N-terminal PH domain followed by a series of EF hands, a catalytic TIM barrel and a C-terminal C2 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-II topology.

Pssm-ID: 175974 [Multi-domain] Cd Length: 128 Bit Score: 40.22 E-value: 7.00e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 147 PKDRNGASDPFVRV------HYNGRTQETSVVKK-SCYPRWNETFDF-----ELekgaseALL-VEAWDWDlVSRNDFLG 213
Cdd:cd00275  18 KGDKGSIVDPYVEVeihglpADDSAKFKTKVVKNnGFNPVWNETFEFdvtvpEL------AFLrFVVYDED-SGDDDFLG 90

Myosin X-like Pleckstrin homology (PH) domain, repeat 3; MyoX, a MyTH-FERM myosin, is a molecular motor that has crucial functions in the transport and/or tethering of integrins in the actin-based extensions known as filopodia, microtubule binding, and in netrin-mediated axon guidance. It functions as a dimer. MyoX walks on bundles of actin, rather than single filaments, unlike the other unconventional myosins. MyoX is present in organisms ranging from humans to choanoflagellates, but not in Drosophila and Caenorhabditis elegans.MyoX consists of a N-terminal motor/head region, a neck made of 3 IQ motifs, and a tail consisting of a coiled-coil domain, a PEST region, 3 PH domains, a myosin tail homology 4 (MyTH4), and a FERM domain at its very C-terminus. The first PH domain in the MyoX tail is a split-PH domain, interupted by the second PH domain such that PH 1a and PH 1b flanks PH 2. The third PH domain (PH 3) follows the PH 1b domain. This cd contains the third MyoX PH repeat. PLEKHH3/Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) member 3 is also part of this CD and like MyoX contains a FERM domain, a MyTH4 domain, and a single PH domain. Not much is known about the function of PLEKHH3. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270109 Cd Length: 126 Bit Score: 40.11 E-value: 7.78e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 528 IHRTKGKGPLASSSF-KKLYFSLTTEALSFAKTSSSKKSTF--IKLASIRAAEKVEEKSFGSSHI-MQVIYaddvGRAQT 603
Cdd:cd13297  19 LYKEGGKGGARGNLTkKKRWFVLTGNSLDYYKSSEKNSLKLgtLVLNSLCSVVPPDEKMAKETGYwTFTVH----GRKHS 94

                        90
                ....*....|....*....
gi 84993718 604 VYLQCKCVNELNQWLSALR 622
Cdd:cd13297  95 FRLYTKLQEEAMRWVNAIQ 113

C2 domain third repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

Pssm-ID: 176010 [Multi-domain] Cd Length: 120 Bit Score: 39.49 E-value: 1.12e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKDRNGASDPFVRVHYNGRTQETSVVKKSCY-PRWNETFDF----ELEKgaseaLLVEAWDWDLVSRN 209
Cdd:cd04045   3 LRLHIRKANDLKNLEGVGKIDPYVRVLVNGIVKGRTVTISNTLnPVWDEVLYVpvtsPNQK-----ITLEVMDYEKVGKD 77

                        90
                ....*....|...
gi 84993718 210 DFLGKVAVNVQRL 222
Cdd:cd04045  78 RSLGSVEINVSDL 90

C2 domain second repeat present in Synaptotagmin 17; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. 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 second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 176055 [Multi-domain] Cd Length: 135 Bit Score: 39.87 E-value: 1.16e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVK-VDNEPIIR---TATVWKTLCPFWGEDYQVHLPPTF---HTVAFYVMDEDALS 79
Cdd:cd08410  16 LNVDIIRAKQLLQTDMSQGSDPFVKIQlVHGLKLIKtkkTSCMRGTIDPFYNESFSFKVPQEElenVSLVFTVYGHNVKS 95

                        90       100
                ....*....|....*....|....*...
gi 84993718  80 RDDVIGKVCLTRdaLASHPKGFSGWTHL 107
Cdd:cd08410  96 SNDFIGRIVIGQ--YSSGPSETNHWRRM 121

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

Pssm-ID: 175981 [Multi-domain] Cd Length: 132 Bit Score: 38.79 E-value: 2.24e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 135 LRCAVLEARDLAPKD---RNGAS-------DPFVRV----HYNGRTqetSVVKKSCYPRWNETFDFELEKGASEALLV-- 198
Cdd:cd04014   6 LKIKICEAVDLKPTDwstRHAVPkkgsqllDPYVSIdvddTHIGKT---STKPKTNSPVWNEEFTTEVHNGRNLELTVfh 82

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 84993718 199 EAwdwdLVSRNDFLGKVAVNVQRLCSAQ--QEEGWFRLQPdqsksrQGK 245
Cdd:cd04014  83 DA----AIGPDDFVANCTISFEDLIQRGsgSFDLWVDLEP------QGK 121

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.

Pssm-ID: 175995 [Multi-domain] Cd Length: 125 Bit Score: 38.57 E-value: 2.46e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 139 VLEARDLAPKD-RNGASDPFVRVHY------NGRtQETSVVKKSCYPRWNETFDFELEKG--ASEALLVEAWDWDLVSRN 209
Cdd:cd04029  21 VKECRNLAYGDeAKKRSNPYVKTYLlpdksrQSK-RKTSIKRNTTNPVYNETLKYSISHSqlETRTLQLSVWHYDRFGRN 99

                        90       100
                ....*....|....*....|....*.
gi 84993718 210 DFLGKVAVNVQRLCSAQQEEGWFRLQ 235
Cdd:cd04029 100 TFLGEVEIPLDSWNFDSQHEECLPLH 125

C2 domain present in plant phospholipase D (PLD); PLD hydrolyzes terminal phosphodiester bonds in diester glycerophospholipids resulting in the degradation of phospholipids. In vitro PLD transfers phosphatidic acid to primary alcohols. In plants PLD plays a role in germination, seedling growth, phosphatidylinositol metabolism, and changes in phospholipid composition. There is a single Ca(2+)/phospholipid-binding C2 domain in PLD. 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.

Pssm-ID: 175982 [Multi-domain] Cd Length: 158 Bit Score: 39.21 E-value: 2.69e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718 152 GASDPFVRVHYNG-RTQETSVVKKSCYPRWNETFDFELEKGASE-ALLVEawDWDLVSrNDFLGKVAVNVQRLCSAQQEE 229
Cdd:cd04015  56 ITSDPYATVDLAGaRVARTRVIENSENPVWNESFHIYCAHYASHvEFTVK--DNDVVG-AQLIGRAYIPVEDLLSGEPVE 132

                        90       100
                ....*....|....*....|....*....
gi 84993718 230 GWFRLQPdqsksRQGKGNLGSLQLEVRLR 258
Cdd:cd04015 133 GWLPILD-----SNGKPPKPGAKIRVSLQ 156

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

Pssm-ID: 176015 [Multi-domain] Cd Length: 105 Bit Score: 37.54 E-value: 3.33e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPiIRTATVWKTLCPFWGEDY 57
Cdd:cd04050   2 LFVYLDSAKNLPLAKSTKEPSPYVELTVGKTT-QKSKVKERTNNPVWEEGF 51

C2 domain second repeat present in Synaptotagmin 12; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Synaptotagmin 12, a member of class 6 synaptotagmins, is located in the brain. It functions are unknown. It, like synaptotagmins 8 and 13, do not have any consensus Ca2+ binding sites. 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.

Pssm-ID: 176051 [Multi-domain] Cd Length: 136 Bit Score: 38.23 E-value: 3.89e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 84993718 118 GEIHLRLEVVPGvhASRLRCAVLEARDLAPKDRNGASDPFVRVHY--NGR---TQETSVVKKSCYPRWNETFDF 186
Cdd:cd08406   2 GEILLSLSYLPT--AERLTVVVVKARNLVWDNGKTTADPFVKVYLlqDGRkisKKKTSVKRDDTNPIFNEAMIF 73

C2 domain second repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.

Pssm-ID: 176017 [Multi-domain] Cd Length: 111 Bit Score: 37.20 E-value: 5.51e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 84993718  15 KNL-PAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDALSRDDVIGKV 87
Cdd:cd04052   1 KGLdTSESKTGLLSPYAELYLNGKLVYTTRVKKKTNNPSWNASTEFLVTDRRKSRVTVVVKDDRDRHDPVLGSV 74

C2 domain third repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

Pssm-ID: 176010 [Multi-domain] Cd Length: 120 Bit Score: 37.18 E-value: 5.99e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 84993718   7 LSIRIVEGKNLPAKDITGSSDPYCIVKVDNEPIIRTATVWKTLCPFWGEDYQVHLPPTFHTVAFYVMDEDALSRDDVIGK 86
Cdd:cd04045   3 LRLHIRKANDLKNLEGVGKIDPYVRVLVNGIVKGRTVTISNTLNPVWDEVLYVPVTSPNQKITLEVMDYEKVGKDRSLGS 82


                .
gi 84993718  87 V 87
Cdd:cd04045  83 V 83