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 320542271  721 PNAEHTRRTDNSLKMWVYEAKNLPPKKRYFCELQLDKTLYGRTSVKLQTDLLFWGEHFDFPDIPEINVITVNVFREVDKK 800
Cdd:cd04013     1 PNRDNSRRTENSLKLWIIEAKGLPPKKRYYCELCLDKTLYARTTSKLKTDTLFWGEHFEFSNLPPVSVITVNLYRESDKK 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 320542271  801 KKRDKYQFVGSVKIPVHDVTSRLPCEQWYPILSDKAGDSLGRtsggggsgSKDKEQLPTLRIKCRFQSTDILPI 874
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 320542271  1927 ESTMRSIIDRLITMEEELRREQLKMSLALSHKQRVIEEQGQQIAALDAANSRLLSALTALRQRY 1990
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 320542271  721 PNAEHTRRTDNSLKMWVYEAKNLPPKKRYFCELQLDKTLYGRTSVKLQTDLLFWGEHFDFPDIPEINVITVNVFREVDKK 800
Cdd:cd04013     1 PNRDNSRRTENSLKLWIIEAKGLPPKKRYYCELCLDKTLYARTTSKLKTDTLFWGEHFEFSNLPPVSVITVNLYRESDKK 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 320542271  801 KKRDKYQFVGSVKIPVHDVTSRLPCEQWYPILSDKAGDSLGRtsggggsgSKDKEQLPTLRIKCRFQSTDILPI 874
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 320542271  615 FTNFFSKKSN-PLKRTKSVTKLERTK------------RGSGGLRGSRSHESLLSSHAVMStiDLSCTGAVGVAPVHQSV 681
Cdd:cd13262     1 ASGFFSRRLKgPLKRTKSVTKLERKSskrlprtrlaraPAGPRLRGSRSHESLLSSSSAAL--DLSADEDVVIRPLHSSI 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 320542271  682 LGRRHCFQVRGGpRGERYYSCGSRQERDLWIYSLRKSIAPNAEHTRRT 729
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 320542271  1927 ESTMRSIIDRLITMEEELRREQLKMSLALSHKQRVIEEQGQQIAALDAANSRLLSALTALRQRY 1990
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 320542271    732 SLKMWVYEAKNLPPKKRY-----FCELQLDKTLY--GRTSVKLQTDLLFWGEHFDFP-DIPEINVITVNVFrevDKKKKR 803
Cdd:smart00239    1 TLTVKIISARNLPPKDKGgksdpYVKVSLDGDPKekKKTKVVKNTLNPVWNETFEFEvPPPELAELEIEVY---DKDRFG 77

                            90       100
                    ....*....|....*....|....*
gi 320542271    804 DKyQFVGSVKIPVHDVTSRLPCEQW 828
Cdd:smart00239   78 RD-DFIGQVTIPLSDLLLGGRHEKL 101

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 320542271   656 SSHAVMSTIDLSctGAVGVAPVHQSVLGRRHCFQVRGGPRGER---YYSCGSRQERDLWIYSLRKSIA 720
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 320542271  721 PNAEHTRRTDNSLKMWVYEAKNLPPKKRYFCELQLDKTLYGRTSVKLQTDLLFWGEHFDFPDIPEINVITVNVFREVDKK 800
Cdd:cd04013     1 PNRDNSRRTENSLKLWIIEAKGLPPKKRYYCELCLDKTLYARTTSKLKTDTLFWGEHFEFSNLPPVSVITVNLYRESDKK 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 320542271  801 KKRDKYQFVGSVKIPVHDVTSRLPCEQWYPILSDKAGDSLGRtsggggsgSKDKEQLPTLRIKCRFQSTDILPI 874
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 320542271  882 TYLKENYKRVCETLEPVIGVKAKEDIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLATKSMEAFLKLTG 961
Cdd:cd04519     8 LLLTESPLALLRELSQVLPVKDKEEVATALLRIFESRGLALEFLRYLVRSEVKNTKNPNTLFRGNSLATKLLDQYMKLVG 87

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271  962 EQYLQDTLSAPINELIQSERDCEVDPTKTSGssaGSLQRQQAALRGAVRGAWQCIFESHKHFPAQLRNCFATFRERLQQL 1041
Cdd:cd04519    88 QEYLKETLSPLIREILESKESCEIDTKLPVG---EDLEENLENLLELVNKLVDRILSSLDRLPPELRYVFKILREFLAER 164

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271 1042 GRQDM--ADNLISASIFLRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQGKENFMEFLNDFLEQEA 1119
Cdd:cd04519   165 FPEEPdeAYQAVSGFLFLRFICPAIVSPELFGLVPDEPSEQARRNLTLISKVLQSLANGVEFGDKEPFMKPLNDFIKSNK 244

                         250
                  ....*....|.
gi 320542271 1120 ARMQQFLEIIS 1130
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 320542271  875 NVYGNFLTYLKE--NYKRVCETLEPVIG--VK-AKEDIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLA 949
Cdd:cd05128     1 QYYEPLLNLLLEslDVPPFTASAVYLLEelVKvDKDDVARPLVRIFLHHGQIVPLLRALASREISKTQDPNTLFRGNSLA 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271  950 TKSMEAFLKLTGEQYLQDTLSAPINELIQSERDCEVDPTKTsgSSAGSLQRQQAALRGAVRGAWQCIFESHKHFPAQLRN 1029
Cdd:cd05128    81 SKCMDEFMKLVGMQYLHETLKPVIDEIFSEKKSCEIDPSKL--KDGEVLETNLANLRGYVERVFKAITSSARRCPTLMCE 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271 1030 CFATFRERLQQlgRQDMADNL----ISASIFLRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANF----TRF 1101
Cdd:cd05128   159 IFSDLRESAAQ--RFPDNEDVpytaVSGFIFLRFFAPAILNPKLFGLREEHPDPQTARTLTLISKTIQTLGNLgsssSGL 236

                         250       260       270
                  ....*....|....*....|....*....|..
gi 320542271 1102 QGKENFMEFLND--FLEQEAARMQQFLEIIST 1131
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 320542271  618 FFSKK-SNPLKRTKSVTKLERTK-----------------RGSGGLRGSRSHESLLSSHAVMSTIDLSCTGAVGVAPVHQ 679
Cdd:cd13375    11 FLSRRlKSSIKRTKSQPKLDRTSsfrqilprfrsadhdraRLMQSFKESHSHESLLSPSSAAEALDLNLDEDSIIKPVHS 90

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271  680 SVLGRRHCFQVRGGpRGERYYSCGSRQERDLWIYSLRKSIAPNAEHTRRTDNSLKMWVYEAKNLPPKKRYFCELQLDKTL 759
Cdd:cd13375    91 SILGQEFCFEVTTA-SGTKCFACRSAAERDKWIENLQRAVKPNKDNSRRVDNVLKLWIIEARELPPKKRYYCELCLDDML 169

                         170       180
                  ....*....|....*....|
gi 320542271  760 YGRTSVKLQTDLLFWGEHFD 779
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 320542271  908 GQALVLLmhAQGLAGAFLTDVVALDLLRVGDQR---------LTFRGNSLATKSMEAFLKLTGEQYLQDTLSAPINELIQ 978
Cdd:cd05391    33 GQDRTLL--ASILLRIFRHEKLESLLLRTLNDReismedeatTLFRATTLASTLMEQYMKATATPFVHHALKDTILKILE 110

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271  979 SERDCEVDPTKTSGSSAGSLQRQQaaLRGAVRGAWQCIFESHKHFPAQLRNCFATFRERLQQL--GRQDMADNLISASIF 1056
Cdd:cd05391   111 SKQSCELNPSKLEKNEDVNTNLEH--LLNILSELVEKIFMAAEILPPTLRYIYGCLQKSVQQKwpTNTTVRTRVVSGFVF 188

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271 1057 LRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQGKENFMEFLNDFLEQEAARMQQFLEIISTRP--- 1133
Cdd:cd05391   189 LRLICPAILNPRMFNIISETPSPTAARTLTLVAKSLQNLANLVEFGAKEPYMEGVNPFIKKNKERMIMFLDELGNVPelp 268

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|...
gi 320542271 1134 ---EHPAPDSILDWAG-------YIDQGKQLSILHSLLSESLAKLPEARQHEL 1176
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 320542271  877 YGNFLTYLKENYKRVCETLEpVIGVKAKEDIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLATKSMEAF 956
Cdd:cd05392     6 YDELLELLIEDPQLLLAIAE-VCPSSEVDLLAQSLLNLFETRNRLLPLISWLIEDEISHTSRAADLFRRNSVATRLLTLY 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271  957 LKLTGEQYLQDTLSAPINELIQSERDCEVDPTKTSGSSagsLQRQQAALRGAVRGAWQCIFESHKHFPAQLRNCFATFRE 1036
Cdd:cd05392    85 AKSVGNKYLRKVLRPLLTEIVDNKDYFEVEKIKPDDEN---LEENADLLMKYAQMLLDSITDSVDQLPPSFRYICNTIYE 161

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271 1037 RLQQLgRQDMADNLISASIFLRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQGKENFMEFLNDFLE 1116
Cdd:cd05392   162 SVSKK-FPDAALIAVGGFLFLRFICPAIVSPESENLLDPPPTPEARRSLILIAKVLQNIANGVLFSLKEPYLESLNEFLK 240

                         250
                  ....*....|....*..
gi 320542271 1117 QEAARMQQFLEIISTRP 1133
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 320542271  906 DIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLATKSMEAFLKLTGEQYLQDTLSAPINELIQSER--DC 983
Cdd:cd05130    41 ELARVLVTLFDSKHLLYQLLWNMFSKEVELADSMQTLFRGNSLASKIMTFCFKVYGATYLQSLLEPLLRTMITSSEwvSY 120

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271  984 EVDPTKTSGSSagSLQRQQAALRGAVRGAWQCIFESHKHFPAQLRNCFATFRERLQQLGRQDMADNLISAsIFLRFLCPA 1063
Cdd:cd05130   121 EVDPTRLEGNE--NLEENQRNLLQLTEKFFHAIISSSDEFPPQLRSVCHCLYQVVSHRFPNSGLGAVGSA-IFLRFINPA 197

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271 1064 ILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQgKENFMEFLNDFLEQEAARMQQFLEIIST------RPEHPA 1137
Cdd:cd05130   198 IVSPYEYGILDREPPPRVKRGLKLMSKILQNIANHVLFT-KEAHMLPFNDFLRNHFEAGRRFFSSIASdcgavdGPSSKY 276

                         250       260       270
                  ....*....|....*....|....*....|
gi 320542271 1138 PDSILDWagyidqgkQLSILHSLLSESLAK 1167
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 320542271  895 LEPVIGVKAKEDIGQALVLLMHAQGLAGAFLTDVVALDLLRVGDQRLTFRGNSLATKSMEAFLKLTGEQYLQDTLSAPIN 974
Cdd:cd05395    31 IDETTTAECRQEVATNLVKLFLGQGLAKEFLDLLFQLELDKTTEPNTLFRSNSLASKSMESFLKVAGMQYLHSVLGPTIN 110

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271  975 ELIQSERDCEVDPTKTSGSSAG--SLQRQQAA----------LRGAVRGAWQCIFESHKHFPAQLRNCFATFRERLQQL- 1041
Cdd:cd05395   111 RVFEEKKYVELDPSKVEIKDVGcsGLHRIQTEsevieqsaqlLQSYLGELLSAISKSVKYCPAVIRATFRQLFKRVQERf 190

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 320542271 1042 -GRQDMADNLISASIF--LRFLCPAILSPSLFNITSELPSARATRNLTLVAKTLQTLANFTRFQG--KENFMEFLNDFLE 1116
Cdd:cd05395   191 pENQHQNVKFIAVTSFlcLRFFSPAIMSPKLFHLREKHADARTSRTLLLLAKAVQNVGNMDTLASraKEAWMAPLQPAIQ 270

                         250
                  ....*....|
gi 320542271 1117 QEAARMQQFL 1126
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 320542271  604 QHQTEHNATSrfTNFFSKKSNPLKRTKSVTK--LERTKRGSGGLRGSR-SHESLlsshAVMSTIDLSCTGAVGVAPVHQS 680
Cdd:cd13374     6 PGKTEPEAAG--PNQGHNVRGLLKRLKEKKKakAESTGTGRDGPPSALgSRESL----ATISELDLGAERDVRVWPLHPS 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 320542271  681 VLGRRHCFQVRGgPRGERYYSCGSRQERDLWIYSLRKSIAPNAEHTRRTDNSLKMWVYEAKNLP 744
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 320542271  614 RFTNFFSKK-SNPLKRTKSVTKLERT--------------KRGSGGLRGSRSHESLLSSHAVMSTIDLSCTGAVGVAPVH 678
Cdd:cd13373     3 KVSGFFSKRlKGSIKRTKSQSKLDRNtsfrlpslrsaddrSRGLPKLKESRSHESLLSPGSAVEALDLGREEKVSVKPLH 82

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 320542271  679 QSVLGRRHCFQVRGGpRGERYYSCGSRQERDLWIYSLRKSIAPNAEHTRRTDNSLKM 735
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 320542271  733 LKMWVYEAKNLPPKKR-----YFCELQLDKTLYGRTSVKLQTDLLFWGEHFDFPDIPEIN-VITVNVFREvDKKKKRDky 806
Cdd:cd00030     1 LRVTVIEARNLPAKDLngksdPYVKVSLGGKQKFKTKVVKNTLNPVWNETFEFPVLDPESdTLTVEVWDK-DRFSKDD-- 77