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 1720390346 446 RVRCLRVLPSERYKELAEFLTFHYARLCGALEPALSAQAKEELAAAMVRVLRATGRAQALVTDLGTAELARCGgREALLF 525
Cdd:cd05136     1 RYQSVDILPLEVYKEFLEYLTNNYLDLCEVLEPVLSVKAKEELATALVHILQSTGKAKEFLTDLVMAEVDRLD-DEHLIF 79

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1720390346 526 RENTLATKAIDEYMKLVAQEYLQDTLGQVVRCLCASTEDCEVDPSKCPT-PELPKHQARLRDSCEEVFENIIHSYK 600
Cdd:cd05136    80 RGNTLATKAMEAYLKLVGQKYLQETLGEFIRALYESEEDCEVDPSKCPPsASLSRNQANLRRSVELAWCKILSSHC 155

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720390346 446 RVRCLRVLPSERYKELAEFLTFHYARLCGALEPALSAQAKEELAAAMVRVLRATGRAQALVTDLGTAELARCGgREALLF 525
Cdd:cd05136     1 RYQSVDILPLEVYKEFLEYLTNNYLDLCEVLEPVLSVKAKEELATALVHILQSTGKAKEFLTDLVMAEVDRLD-DEHLIF 79

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1720390346 526 RENTLATKAIDEYMKLVAQEYLQDTLGQVVRCLCASTEDCEVDPSKCPT-PELPKHQARLRDSCEEVFENIIHSYK 600
Cdd:cd05136    80 RGNTLATKAMEAYLKLVGQKYLQETLGEFIRALYESEEDCEVDPSKCPPsASLSRNQANLRRSVELAWCKILSSHC 155

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 1720390346 322 PSQDNVERQEMWLTVWVHEAKGLPratvPGVR--AELWLDGALLARTAPRAGPGQLFWAERFHFEALPPARRLSLRL-RS 398
Cdd:cd04013     1 PNRDNSRRTENSLKLWIIEAKGLP----PKKRyyCELCLDKTLYARTTSKLKTDTLFWGEHFEFSNLPPVSVITVNLyRE 76

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1720390346 399 AG-----PAGATVGRVVLELDEVSiPRAPaagLERWFPVLGAPAGAV------------LRARIRVRCLRVLP 454
Cdd:cd04013    77 SDkkkkkDKSQLIGTVNIPVTDVS-SRQF---VEKWYPVSTPKGNGKsggkegkgespsIRIKARYQSTRVLP 145

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.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 1720390346  276 VWPLHPSLLGEPYCFQV-TWAGGSLCFSCRSSAERDRWIEDLRR 318
Cdd:smart00233  56 REAPDPDSSKKPHCFEIkTSDRKTLLLQAESEEEREKWVEALRK 99

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720390346 446 RVRCLRVLPSERYKELAEFLTFHYARLCGALEPALSAQAKEELAAAMVRVLRATGRAQALVTDLGTAELARCGgREALLF 525
Cdd:cd05136     1 RYQSVDILPLEVYKEFLEYLTNNYLDLCEVLEPVLSVKAKEELATALVHILQSTGKAKEFLTDLVMAEVDRLD-DEHLIF 79

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1720390346 526 RENTLATKAIDEYMKLVAQEYLQDTLGQVVRCLCASTEDCEVDPSKCPT-PELPKHQARLRDSCEEVFENIIHSYK 600
Cdd:cd05136    80 RGNTLATKAMEAYLKLVGQKYLQETLGEFIRALYESEEDCEVDPSKCPPsASLSRNQANLRRSVELAWCKILSSHC 155

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 1720390346 208 PGKTEPEAAGSNQVHNVRKLLKRLKEKKrAKSELGAYTPRDGPPSALGSRESLATLSE--LDLGAERDVRVWPLHPSLLG 285
Cdd:cd13262     2 SGFFSRRLKGPLKRTKSVTKLERKSSKR-LPRTRLARAPAGPRLRGSRSHESLLSSSSaaLDLSADEDVVIRPLHSSILG 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1720390346 286 EPYCFQVTWAGGSLCFSCRSSAERDRWIEDLRRQFQPSQDNVER 329
Cdd:cd13262    81 RKHCFQVTTSEGTRCFSCRSAAERDRWIEDLRRAAQPNKDNCRR 124

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 1720390346 256 SRESLATLSE----LDLGAERDVRVWPLHPSLLGEPYCFQVTWAGGSLCFSCRSSAERDRWIEDLRRQFQPSQDNVERQE 331
Cdd:cd13375    61 SHESLLSPSSaaeaLDLNLDEDSIIKPVHSSILGQEFCFEVTTASGTKCFACRSAAERDKWIENLQRAVKPNKDNSRRVD 140

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720390346 332 MWLTVWVHEAKGLPratvPGVR--AELWLDGALLARTAPRAGPGQLFWAErfHFE 384
Cdd:cd13375   141 NVLKLWIIEARELP----PKKRyyCELCLDDMLYARTTSKPRTDTVFWGE--HFE 189

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 1720390346 256 SRESL----ATLSELDLGAERDVRVWPLHPSLLGEPYCFQVTWAGGSLCFSCRSSAERDRWIEDLRRQFQPSQDNVERQE 331
Cdd:cd13373    54 SHESLlspgSAVEALDLGREEKVSVKPLHSSILGQDFCFEVTYSSGSKCFSCSSAAERDKWMENLRRTVQPNKDNCRRAE 133

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 1720390346 458 YKELAEFLT------FHYARLCGALEpALSAQAKEELAAAMVRVLRATGRAQALVTDLGTAELARCGgREALLFRENTLA 531
Cdd:cd05128     3 YEPLLNLLLesldvpPFTASAVYLLE-ELVKVDKDDVARPLVRIFLHHGQIVPLLRALASREISKTQ-DPNTLFRGNSLA 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1720390346 532 TKAIDEYMKLVAQEYLQDTLGQVVRCLCASTEDCEVDPSKCPTPE-LPKHQARLRDSCEEVFENIIHS 598
Cdd:cd05128    81 SKCMDEFMKLVGMQYLHETLKPVIDEIFSEKKSCEIDPSKLKDGEvLETNLANLRGYVERVFKAITSS 148

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720390346 485 KEELAAAMVRVLRATGRAQALVTDLGTAELARCGGREALlFRENTLATKAIDEYMKLVAQEYLQDTLGQVVRCLCASTED 564
Cdd:cd05134    35 KQEAAIPLVRLFLHYGKIVPFISAIASAEVNRTQDPNTI-FRGNSLTSKCIDETMKLAGMHYLQVTLKPIIDEICQEHKP 113

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1720390346 565 CEVDPSKCPTPE-LPKHQARLRDSCEEVFENIIHS 598
Cdd:cd05134   114 CEIDPVKLKDGEnLENNRENLRQYVDRIFRVITKS 148

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720390346 492 MVRVLRATGRAQALVTDLgtAELARCGGREA-LLFRENTLATKAIDEYMKLVAQEYLQDTLGQVVRCLCASTEDCEVDPS 570
Cdd:cd05394    42 LVRLLLHHNKLVPFVAAV--AALDLKDTQEAnTIFRGNSLATRCLDEMMKIVGKHYLKVTLKPVLDEICESPKPCEIDPI 119

                          90       100
                  ....*....|....*....|....*....
gi 1720390346 571 KCPTPE-LPKHQARLRDSCEEVFENIIHS 598
Cdd:cd05394   120 KLKEGDnVENNKENLRYYVDKVFFSIVKS 148

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720390346 476 LEPALSAQAKEELAAAMVRVLRATGRAQALVTDLGTAELARCGGREALlFRENTLATKAIDEYMKLVAQEYLQDTLGQVV 555
Cdd:cd05135    31 LEEVTTGESRQDVATKLVKIFLGQGLVVPFLDYLNTREVGRTTDPNTL-FRSNSLASKSMEQFMKVVGMPYLHEVLKPVI 109

                          90
                  ....*....|....*.
gi 1720390346 556 RCLCASTEDCEVDPSK 571
Cdd:cd05135   110 NRIFEEKKYVELDPCK 125

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1720390346 524 LFRENTLATKAIDEYMKL-VAQEYLQDTLGQVVRCLCASTE-DCEVDPSK 571
Cdd:pfam00616  19 LLRGNSLVSKLLETYNRRpRGQEYLKKVLGPLVRKIIEDEDlDLESDPRK 68

C2 domain present in RAS p21 protein activator 1 (RasA1); RasA1 is a GAP1 (GTPase activating protein 1), a Ras-specific GAP member, 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. RasA1 contains a C2 domain, a Ras-GAP domain, a pleckstrin homology (PH)-like domain, a SH3 domain, and 2 SH2 domains. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have a type-I topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720390346 329 RQEMWLTVWVHEAKGLPRATVPGVRAELWLDGALLARTAPRAGPGQLfWAERFHFEALPP-ARRLSLRLRSAGPAG--AT 405
Cdd:cd08400     1 RQVRSLQLNVLEAHKLPVKHVPHPYCVISLNEVKVARTKVREGPNPV-WSEEFVFDDLPPdVNSFTISLSNKAKRSkdSE 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1720390346 406 VGRVVLELDevSIPRAPAagLERWFPVLGA---PAGAVLRARIRVR 448
Cdd:cd08400    80 IAEVTVQLS--KLQNGQE--TDEWYPLSSAsplKGGEWGSLRIRAR 121

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.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 1720390346  276 VWPLHPSLLGEPYCFQV-TWAGGSLCFSCRSSAERDRWIEDLRR 318
Cdd:smart00233  56 REAPDPDSSKKPHCFEIkTSDRKTLLLQAESEEEREKWVEALRK 99

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 1720390346 334 LTVWVHEAKGLPRATVPGVR---AELWLDGALLARTAPRagPGQL--FWAERFHFEALPPA-RRLSLRLRSAGPAGA--T 405
Cdd:cd00030     1 LRVTVIEARNLPAKDLNGKSdpyVKVSLGGKQKFKTKVV--KNTLnpVWNETFEFPVLDPEsDTLTVEVWDKDRFSKddF 78

                          90       100
                  ....*....|....*....|....*.
gi 1720390346 406 VGRVVLELDEVSIPRAPAaglERWFP 431
Cdd:cd00030    79 LGEVEIPLSELLDSGKEG---ELWLP 101