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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  277 PNAEHTRRTDNSLKMWVYEAKNLPPKKRYFCELQLDKTLYGRTSVKLQTDLLFWGEHFDFPDIPEINVITVNVFREVDKK 356
Cdd:cd04013     1 PNRDNSRRTENSLKLWIIEAKGLPPKKRYYCELCLDKTLYARTTSKLKTDTLFWGEHFEFSNLPPVSVITVNLYRESDKK 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 665392117  357 KKRDKYQFVGSVKIPVHDVTSRLPCEQWYPILSDKAGDSLGRtsggggsgSKDKEQLPTLRIKCRFQSTDILPI 430
Cdd:cd04013    81 KKKDKSQLIGTVNIPVTDVSSRQFVEKWYPVSTPKGNGKSGG--------KEGKGESPSIRIKARYQSTRVLPL 146

Domain of unknown function (DUF3498); This presumed domain is functionally uncharacterized. This domain is found in eukaryotes. This domain is typically between 433 to 538 amino acids in length. This domain is found associated with pfam00616, pfam00168. This domain has two conserved sequence motifs: DLQ and PLSFQNP.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 665392117  1483 ESTMRSIIDRLITMEEELRREQLKMSLALSHKQRVIEEQGQQIAALDAANSRLLSALTALRQRY 1546
Cdd:pfam12004  448 DSQMKSIISRLMAVEEELKKDHAEMQAVIDSKQKIIDAQEKRIASLDAANARLMSALTQLKERY 511

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  277 PNAEHTRRTDNSLKMWVYEAKNLPPKKRYFCELQLDKTLYGRTSVKLQTDLLFWGEHFDFPDIPEINVITVNVFREVDKK 356
Cdd:cd04013     1 PNRDNSRRTENSLKLWIIEAKGLPPKKRYYCELCLDKTLYARTTSKLKTDTLFWGEHFEFSNLPPVSVITVNLYRESDKK 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 665392117  357 KKRDKYQFVGSVKIPVHDVTSRLPCEQWYPILSDKAGDSLGRtsggggsgSKDKEQLPTLRIKCRFQSTDILPI 430
Cdd:cd04013    81 KKKDKSQLIGTVNIPVTDVSSRQFVEKWYPVSTPKGNGKSGG--------KEGKGESPSIRIKARYQSTRVLPL 146

Synaptic Ras-GTPase activating protein family Pleckstrin homology (PH) domain; The RasSynGAP family is composed of members: DAB2IP, nGAP, and SynGAP. Neuronal growth-associated proteins (nGAPs) are growth cone markers found in multiple types of neurons. There are many nGAPs including Cap1 (Adenylate cyclase-associated protein 1), Capzb (Capping protein (actin filament) muscle Z-line, beta), Clptm1 (Cleft lip and palate associated transmembrane protein 1), Cotl1 (Coactosin-like 1), Crmp1 (Collapsin response mediator protein 1), Cyfip1 (Cytoplasmic FMR1 interacting protein 1), Fabp7 (Fatty acid binding protein 7, brain), Farp2 (FERM, RhoGEF and pleckstrin domain protein 2), Gap43 (Growth associated protein 43), Gnao1 (Guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O), Gnai2 (Guanine nucleotide binding protein (G protein), alpha inhibiting 2), Pacs1 (Phosphofurin acidic cluster sorting protein 1), Rtn1 (Reticulon 1), Sept2 (Septin 2), Snap25 (Synaptosomal-associated protein 25), Strap (Serine/threonine kinase receptor associated protein), Stx7 (Syntaxin 7), and Tmod2 (Tropomodulin 2). SynGAP, a neuronal Ras-GAP, has been shown display both Ras-GAP activity and Ras-related protein (Rap)-GAP activity. Saccharomyces cerevisiae Bud2 and GAP1 members CAPRI (Ca2+-promoted Ras inactivator) and RASAL (Ras-GTPase-activating-like protein) also possess this dual activity. Human DOC-2/DAB2-interacting protein (DAB2IP) is encoded by a tumor suppressor gene and a newly recognized member of the Ras-GTPase-activating family. DAB2IP is a critical component of many signal transduction pathways mediated by Ras and tumor necrosis factors including apoptosis pathways, and it is involved in the formation of many types of tumors. DAB2IP participates in regulation of gene expression and pluripotency of cells. It has been reported that DAB2IP was expressed in different tumor tissues. Little information is available concerning the expression levels of DAB2IP in normal tissues and cells, however, and no studies of its expression patterns during the development of human embryos have been reported. DAB2IP was expressed primarily in cell cytoplasm throughout the fetal development. The expression levels varied among tissues and different gestational ages. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  171 FTNFFSKKSN-PLKRTKSVTKLERTK------------RGSGGLRGSRSHESLLSSHAVMStiDLSCTGAVGVAPVHQSV 237
Cdd:cd13262     1 ASGFFSRRLKgPLKRTKSVTKLERKSskrlprtrlaraPAGPRLRGSRSHESLLSSSSAAL--DLSADEDVVIRPLHSSI 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 665392117  238 LGRRHCFQVRGGpRGERYYSCGSRQERDLWIYSLRKSIAPNAEHTRRT 285
Cdd:cd13262    79 LGRKHCFQVTTS-EGTRCFSCRSAAERDRWIEDLRRAAQPNKDNCRRT 125

Domain of unknown function (DUF3498); This presumed domain is functionally uncharacterized. This domain is found in eukaryotes. This domain is typically between 433 to 538 amino acids in length. This domain is found associated with pfam00616, pfam00168. This domain has two conserved sequence motifs: DLQ and PLSFQNP.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 665392117  1483 ESTMRSIIDRLITMEEELRREQLKMSLALSHKQRVIEEQGQQIAALDAANSRLLSALTALRQRY 1546
Cdd:pfam12004  448 DSQMKSIISRLMAVEEELKKDHAEMQAVIDSKQKIIDAQEKRIASLDAANARLMSALTQLKERY 511

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117    288 SLKMWVYEAKNLPPKKRY-----FCELQLDKTLY--GRTSVKLQTDLLFWGEHFDFP-DIPEINVITVNVFrevDKKKKR 359
Cdd:smart00239    1 TLTVKIISARNLPPKDKGgksdpYVKVSLDGDPKekKKTKVVKNTLNPVWNETFEFEvPPPELAELEIEVY---DKDRFG 77

                            90       100
                    ....*....|....*....|....*
gi 665392117    360 DKyQFVGSVKIPVHDVTSRLPCEQW 384
Cdd:smart00239   78 RD-DFIGQVTIPLSDLLLGGRHEKL 101

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 665392117   212 SSHAVMSTIDLSctGAVGVAPVHQSVLGRRHCFQVRGGPRGER---YYSCGSRQERDLWIYSLRKSIA 276
Cdd:pfam00169   40 KSKEPKGSISLS--GCEVVEVVASDSPKRKFCFELRTGERTGKrtyLLQAESEEERKDWIKAIQSAIR 105

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  277 PNAEHTRRTDNSLKMWVYEAKNLPPKKRYFCELQLDKTLYGRTSVKLQTDLLFWGEHFDFPDIPEINVITVNVFREVDKK 356
Cdd:cd04013     1 PNRDNSRRTENSLKLWIIEAKGLPPKKRYYCELCLDKTLYARTTSKLKTDTLFWGEHFEFSNLPPVSVITVNLYRESDKK 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 665392117  357 KKRDKYQFVGSVKIPVHDVTSRLPCEQWYPILSDKAGDSLGRtsggggsgSKDKEQLPTLRIKCRFQSTDILPI 430
Cdd:cd04013    81 KKKDKSQLIGTVNIPVTDVSSRQFVEKWYPVSTPKGNGKSGG--------KEGKGESPSIRIKARYQSTRVLPL 146

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  438 TYLKENYKRVCETLEPVIGVKAKEDIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLATKSMEAFLKLTG 517
Cdd:cd04519     8 LLLTESPLALLRELSQVLPVKDKEEVATALLRIFESRGLALEFLRYLVRSEVKNTKNPNTLFRGNSLATKLLDQYMKLVG 87

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  518 EQYLQDTLSAPINELIQSERDCEVDPTKTSGssaGSLQRQQAALRGAVRGAWQCIFESHKHFPAQLRNCFATFRERLQQL 597
Cdd:cd04519    88 QEYLKETLSPLIREILESKESCEIDTKLPVG---EDLEENLENLLELVNKLVDRILSSLDRLPPELRYVFKILREFLAER 164

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  598 GRQDM--ADNLISASIFLRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQGKENFMEFLNDFLEQEA 675
Cdd:cd04519   165 FPEEPdeAYQAVSGFLFLRFICPAIVSPELFGLVPDEPSEQARRNLTLISKVLQSLANGVEFGDKEPFMKPLNDFIKSNK 244

                         250
                  ....*....|.
gi 665392117  676 ARMQQFLEIIS 686
Cdd:cd04519   245 PKLKQFLDELS 255

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  431 NVYGNFLTYLKE--NYKRVCETLEPVIG--VK-AKEDIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLA 505
Cdd:cd05128     1 QYYEPLLNLLLEslDVPPFTASAVYLLEelVKvDKDDVARPLVRIFLHHGQIVPLLRALASREISKTQDPNTLFRGNSLA 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  506 TKSMEAFLKLTGEQYLQDTLSAPINELIQSERDCEVDPTKTsgSSAGSLQRQQAALRGAVRGAWQCIFESHKHFPAQLRN 585
Cdd:cd05128    81 SKCMDEFMKLVGMQYLHETLKPVIDEIFSEKKSCEIDPSKL--KDGEVLETNLANLRGYVERVFKAITSSARRCPTLMCE 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  586 CFATFRERLQQlgRQDMADNL----ISASIFLRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANF----TRF 657
Cdd:cd05128   159 IFSDLRESAAQ--RFPDNEDVpytaVSGFIFLRFFAPAILNPKLFGLREEHPDPQTARTLTLISKTIQTLGNLgsssSGL 236

                         250       260       270
                  ....*....|....*....|....*....|..
gi 665392117  658 QGKENFMEFLND--FLEQEAARMQQFLEIIST 687
Cdd:cd05128   237 GVKEAYMSPLYErfTDEQHVDAVKKFLDRISS 268

Synaptic Ras-GTPase activating protein Pleckstrin homology (PH) domain; SynGAP is a member of the RasSynGAP family along with DOC-2/DAB2-interacting protein (DAB2IP) and neuronal growth-associated protein (nGAP/RASAL2). SynGAP, a neuronal Ras-GAP, has been shown display both Ras-GAP activity and Ras-related protein (Rap)-GAP activity. Saccharomyces cerevisiae Bud2 and GAP1 members CAPRI (Ca2+-promoted Ras inactivator) and RASAL (Ras-GTPase-activating-like protein) also possess this dual activity. Human DOC-2/DAB2-interacting protein (DAB2IP) is encoded by a tumor suppressor gene and a newly recognized member of the Ras-GTPase-activating family. Members here include mammals, amphibians, and bony 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  174 FFSKK-SNPLKRTKSVTKLERTK-----------------RGSGGLRGSRSHESLLSSHAVMSTIDLSCTGAVGVAPVHQ 235
Cdd:cd13375    11 FLSRRlKSSIKRTKSQPKLDRTSsfrqilprfrsadhdraRLMQSFKESHSHESLLSPSSAAEALDLNLDEDSIIKPVHS 90

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  236 SVLGRRHCFQVRGGpRGERYYSCGSRQERDLWIYSLRKSIAPNAEHTRRTDNSLKMWVYEAKNLPPKKRYFCELQLDKTL 315
Cdd:cd13375    91 SILGQEFCFEVTTA-SGTKCFACRSAAERDKWIENLQRAVKPNKDNSRRVDNVLKLWIIEARELPPKKRYYCELCLDDML 169

                         170       180
                  ....*....|....*....|
gi 665392117  316 YGRTSVKLQTDLLFWGEHFD 335
Cdd:cd13375   170 YARTTSKPRTDTVFWGEHFE 189

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  464 GQALVLLmhAQGLAGAFLTDVVALDLLRVGDQR---------LTFRGNSLATKSMEAFLKLTGEQYLQDTLSAPINELIQ 534
Cdd:cd05391    33 GQDRTLL--ASILLRIFRHEKLESLLLRTLNDReismedeatTLFRATTLASTLMEQYMKATATPFVHHALKDTILKILE 110

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  535 SERDCEVDPTKTSGSSAGSLQRQQaaLRGAVRGAWQCIFESHKHFPAQLRNCFATFRERLQQL--GRQDMADNLISASIF 612
Cdd:cd05391   111 SKQSCELNPSKLEKNEDVNTNLEH--LLNILSELVEKIFMAAEILPPTLRYIYGCLQKSVQQKwpTNTTVRTRVVSGFVF 188

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  613 LRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQGKENFMEFLNDFLEQEAARMQQFLEIISTRP--- 689
Cdd:cd05391   189 LRLICPAILNPRMFNIISETPSPTAARTLTLVAKSLQNLANLVEFGAKEPYMEGVNPFIKKNKERMIMFLDELGNVPelp 268

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|...
gi 665392117  690 ---EHPAPDSILDWAG-------YIDQGKQLSILHSLLSESLAKLPEARQHEL 732
Cdd:cd05391   269 dttEHSRTDLSRDLAAlheicvaHSDELRTLSNERGALKKLLAVTELLQQKQN 321

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  433 YGNFLTYLKENYKRVCETLEpVIGVKAKEDIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLATKSMEAF 512
Cdd:cd05392     6 YDELLELLIEDPQLLLAIAE-VCPSSEVDLLAQSLLNLFETRNRLLPLISWLIEDEISHTSRAADLFRRNSVATRLLTLY 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  513 LKLTGEQYLQDTLSAPINELIQSERDCEVDPTKTSGSSagsLQRQQAALRGAVRGAWQCIFESHKHFPAQLRNCFATFRE 592
Cdd:cd05392    85 AKSVGNKYLRKVLRPLLTEIVDNKDYFEVEKIKPDDEN---LEENADLLMKYAQMLLDSITDSVDQLPPSFRYICNTIYE 161

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  593 RLQQLgRQDMADNLISASIFLRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQGKENFMEFLNDFLE 672
Cdd:cd05392   162 SVSKK-FPDAALIAVGGFLFLRFICPAIVSPESENLLDPPPTPEARRSLILIAKVLQNIANGVLFSLKEPYLESLNEFLK 240

                         250
                  ....*....|....*..
gi 665392117  673 QEAARMQQFLEIISTRP 689
Cdd:cd05392   241 KNSDRIQQFLSEVSTIP 257

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  462 DIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLATKSMEAFLKLTGEQYLQDTLSAPINELIQSER--DC 539
Cdd:cd05130    41 ELARVLVTLFDSKHLLYQLLWNMFSKEVELADSMQTLFRGNSLASKIMTFCFKVYGATYLQSLLEPLLRTMITSSEwvSY 120

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  540 EVDPTKTSGSSagSLQRQQAALRGAVRGAWQCIFESHKHFPAQLRNCFATFRERLQQLGRQDMADNLISAsIFLRFLCPA 619
Cdd:cd05130   121 EVDPTRLEGNE--NLEENQRNLLQLTEKFFHAIISSSDEFPPQLRSVCHCLYQVVSHRFPNSGLGAVGSA-IFLRFINPA 197

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  620 ILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQgKENFMEFLNDFLEQEAARMQQFLEIIST------RPEHPA 693
Cdd:cd05130   198 IVSPYEYGILDREPPPRVKRGLKLMSKILQNIANHVLFT-KEAHMLPFNDFLRNHFEAGRRFFSSIASdcgavdGPSSKY 276

                         250       260       270
                  ....*....|....*....|....*....|
gi 665392117  694 PDSILDWagyidqgkQLSILHSLLSESLAK 723
Cdd:cd05130   277 LSFINDA--------NVLALHRLLWNNQEK 298

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  451 LEPVIGVKAKEDIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLATKSMEAFLKLTGEQYLQDTLSAPIN 530
Cdd:cd05395    31 IDETTTAECRQEVATNLVKLFLGQGLAKEFLDLLFQLELDKTTEPNTLFRSNSLASKSMESFLKVAGMQYLHSVLGPTIN 110

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  531 ELIQSERDCEVDPTKTSGSSAG--SLQRQQAA----------LRGAVRGAWQCIFESHKHFPAQLRNCFATFRERLQQL- 597
Cdd:cd05395   111 RVFEEKKYVELDPSKVEIKDVGcsGLHRIQTEsevieqsaqlLQSYLGELLSAISKSVKYCPAVIRATFRQLFKRVQERf 190

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  598 -GRQDMADNLISASIF--LRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQG--KENFMEFLNDFLE 672
Cdd:cd05395   191 pENQHQNVKFIAVTSFlcLRFFSPAIMSPKLFHLREKHADARTSRTLLLLAKAVQNVGNMDTLASraKEAWMAPLQPAIQ 270

                         250
                  ....*....|
gi 665392117  673 QEAARMQQFL 682
Cdd:cd05395   271 QGVAQLKDFI 280

RAS protein activator like-3 Pleckstrin homology (PH) domain; RASAL3 is thought to be a Ras GTPase-activating protein. It is involved in positive regulation of Ras GTPase activity and of small GTPase mediated signal transduction as well as negative regulation of Ras protein signal transduction. It contains a PH domain, a C2 domain, and a Ras-GAP 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  160 QHQTEHNATSrfTNFFSKKSNPLKRTKSVTK--LERTKRGSGGLRGSR-SHESLlsshAVMSTIDLSCTGAVGVAPVHQS 236
Cdd:cd13374     6 PGKTEPEAAG--PNQGHNVRGLLKRLKEKKKakAESTGTGRDGPPSALgSRESL----ATISELDLGAERDVRVWPLHPS 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 665392117  237 VLGRRHCFQVRGgPRGERYYSCGSRQERDLWIYSLRKSIAPNAEHTRRTDNSLKMWVYEAKNLP 300
Cdd:cd13374    80 LLGEPHCFQVTW-PGGSRCFSCRSAAERDRWIEDLRRSFQPHQDNVEREETWLSVWVHEAKGLP 142

Neuronal growth-associated proteins Pleckstrin homology (PH) domain; nGAP (also called RASAL2/RAS protein activator like-3) is a member of the RasSynGAP family along with DOC-2/DAB2-interacting protein (DAB2IP) and synaptic RasGAP (SynGAP). nGAPs are growth cone markers found in multiple types of neurons. There are many nGAPs including Cap1 (Adenylate cyclase-associated protein 1), Capzb (Capping protein (actin filament) muscle Z-line, beta), Clptm1 (Cleft lip and palate associated transmembrane protein 1), Cotl1 (Coactosin-like 1), Crmp1 (Collapsin response mediator protein 1), Cyfip1 (Cytoplasmic FMR1 interacting protein 1), Fabp7 (Fatty acid binding protein 7, brain), Farp2 (FERM, RhoGEF and pleckstrin domain protein 2), Gap43 (Growth associated protein 43), Gnao1 (Guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O), Gnai2 (Guanine nucleotide binding protein (G protein), alpha inhibiting 2), Pacs1 (Phosphofurin acidic cluster sorting protein 1), Rtn1 (Reticulon 1), Sept2 (Septin 2), Snap25 (Synaptosomal-associated protein 25), Strap (Serine/threonine kinase receptor associated protein), Stx7 (Syntaxin 7), and Tmod2 (Tropomodulin 2). PH domains are only found in eukaryotes. They 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  170 RFTNFFSKK-SNPLKRTKSVTKLERT--------------KRGSGGLRGSRSHESLLSSHAVMSTIDLSCTGAVGVAPVH 234
Cdd:cd13373     3 KVSGFFSKRlKGSIKRTKSQSKLDRNtsfrlpslrsaddrSRGLPKLKESRSHESLLSPGSAVEALDLGREEKVSVKPLH 82

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 665392117  235 QSVLGRRHCFQVRGGpRGERYYSCGSRQERDLWIYSLRKSIAPNAEHTRRTDNSLKM 291
Cdd:cd13373    83 SSILGQDFCFEVTYS-SGSKCFSCSSAAERDKWMENLRRTVQPNKDNCRRAENVLRL 138

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665392117  289 LKMWVYEAKNLPPKKR-----YFCELQLDKTLYGRTSVKLQTDLLFWGEHFDFPDIPEIN-VITVNVFREvDKKKKRDky 362
Cdd:cd00030     1 LRVTVIEARNLPAKDLngksdPYVKVSLGGKQKFKTKVVKNTLNPVWNETFEFPVLDPESdTLTVEVWDK-DRFSKDD-- 77