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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666 179 SSSGRRDPKSIEQPILLKEGFMIKRAQGRKRFGMKNFKKRWFRLTNHEFTYQKSKGDQPLCNIPIENILAVERLEEESFR 258
Cdd:cd13371    1 SSSGRRDHKSIEQPILLKEGFMIKRAQGRKRFGMKNFKKRWFRLTNHEFTYHKSKGDHPLCSIPIENILAVERLEEESFK 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 149057666 259 MKNMFQVIQPERALYIQANNCVEAKDWIDILTKVSQCNQKRLTVF 303
Cdd:cd13371   81 MKNMFQVIQPERALYIQANNCVEAKDWIDILTKVSQCNKKRLTVY 125

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666 179 SSSGRRDPKSIEQPILLKEGFMIKRAQGRKRFGMKNFKKRWFRLTNHEFTYQKSKGDQPLCNIPIENILAVERLEEESFR 258
Cdd:cd13371    1 SSSGRRDHKSIEQPILLKEGFMIKRAQGRKRFGMKNFKKRWFRLTNHEFTYHKSKGDHPLCSIPIENILAVERLEEESFK 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 149057666 259 MKNMFQVIQPERALYIQANNCVEAKDWIDILTKVSQCNQKRLTVF 303
Cdd:cd13371   81 MKNMFQVIQPERALYIQANNCVEAKDWIDILTKVSQCNKKRLTVY 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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666    5 GMHYLHVTLKPTIEEICQSH-KSCEIDPVK----------LKDGEN--------------------LENNMESLRQYVDR 53
Cdd:pfam00616  39 GQEYLKKVLGPLVRKIIEDEdLDLESDPRKiyeslinqeeLKTGRSdlprdvspeeaiedpevrqiFEDNLQKLRELADE 118

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666   54 IFSVITKSGVSCPTVMCDIFFSLREAAAKRFQD-DLDVRYTAVSSFIFLRFFAPAILSPNLFQLTPHHTDPQTSRTLTLI 132
Cdd:pfam00616 119 FLDAIYSSLNQLPYGIRYICKQLYELLEEKFPDaSEEEILNAIGGFLFLRFFCPAIVNPDLFGLVDHQISPKQRRNLTLI 198

                  ....*....
gi 149057666  133 SKTIQTLGS 141
Cdd:pfam00616 199 AKVLQNLAN 207

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        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666   194 LLKEGFMIKRAQGRKrfgmKNFKKRWFRLTNHEFTYQKSKGDQ----PLCNIPIENILAVERLEEESFRMKNMFQVIQPE 269
Cdd:smart00233   1 VIKEGWLYKKSGGGK----KSWKKRYFVLFNSTLLYYKSKKDKksykPKGSIDLSGCTVREAPDPDSSKKPHCFEIKTSD 76

                           90       100
                   ....*....|....*....|....*.
gi 149057666   270 RA-LYIQANNCVEAKDWIDILTKVSQ 294
Cdd:smart00233  77 RKtLLLQAESEEEREKWVEALRKAIA 102

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

                          10        20
                  ....*....|....*....|....*...
gi 149057666  303 FHPSAYLNGHWLCCRASSDTAIGCTPCT 330
Cdd:pfam00779   2 YHPGAFVDGKWLCCKQTDKNAPGCSPVT 29

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 149057666   1 MKLAGMHYLHVTLKPTIEEICQSHKSCEIDPVKLKDGENLENNMESLRQYVDRIFSVITKSGVSCPTVMCDIFFSLREAA 80
Cdd:cd05128   88 MKLVGMQYLHETLKPVIDEIFSEKKSCEIDPSKLKDGEVLETNLANLRGYVERVFKAITSSARRCPTLMCEIFSDLRESA 167

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666  81 AKRFQDDLDVRYTAVSSFIFLRFFAPAILSPNLFQLTPHHTDPQTSRTLTLISKTIQTLGSLSKSKSA-SFKESYMATFY 159
Cdd:cd05128  168 AQRFPDNEDVPYTAVSGFIFLRFFAPAILNPKLFGLREEHPDPQTARTLTLISKTIQTLGNLGSSSSGlGVKEAYMSPLY 247

                        170       180
                 ....*....|....*....|..
gi 149057666 160 EFFNEQKYADAVKNFLDLISSS 181
Cdd:cd05128  248 ERFTDEQHVDAVKKFLDRISSV 269

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 149057666   1 MKLAGMHYLHVTLKPTIEEICQSHKSCEIDPVKLKDGENLENNMESLRQYVDRIFSVITKSGVSCPTVMCDIFFSLREAA 80
Cdd:cd05394   88 MKIVGKHYLKVTLKPVLDEICESPKPCEIDPIKLKEGDNVENNKENLRYYVDKVFFSIVKSSMSCPTLMCDVFRSLRHLA 167

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666  81 AKRFQDDLDVRYTAVSSFIFLRFFAPAILSPNLFQLTPHHTDPQTSRTLTLISKTIQTLG---SLSKSKSASFKESYMAT 157
Cdd:cd05394  168 VKRFPNDPHVQYSAVSSFVFLRFFAVAVVSPHTFQLRPHHPDAQTSRTLTLISKTIQTLGswgSLSKSKLSSFKETFMCD 247

                        170       180
                 ....*....|....*....|....
gi 149057666 158 FYEFFNEQKYADAVKNFLDLISSS 181
Cdd:cd05394  248 FFKMFQEEKYIEKVKKFLDEISST 271

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666 179 SSSGRRDPKSIEQPILLKEGFMIKRAQGRKRFGMKNFKKRWFRLTNHEFTYQKSKGDQPLCNIPIENILAVERLEEESFR 258
Cdd:cd13370    1 SSTESKESSGVSESVHLKEGEMHKRAQGRTRIGKKNFKKRWFCLTSRELTYHKQKGKEAIFTIPVKNILAVEKLEESAFN 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 149057666 259 MKNMFQVIQPERALYIQANNCVEAKDWIDILTKVSQCNQKRLTVFHPSAYLNG 311
Cdd:cd13370   81 KKNMFQVIHSEKPLYVQANNCVEANEWIEVLSRVSRCNQKRLSFYHPSAYLGG 133

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 149057666   1 MKLAGMHYLHVTLKPTIEEICQSHKSCEIDPvKLKDGENLENNMESLRQYVDRIFSVITKSGVSCPTVMCDIFFSLREAA 80
Cdd:cd04519   83 MKLVGQEYLKETLSPLIREILESKESCEIDT-KLPVGEDLEENLENLLELVNKLVDRILSSLDRLPPELRYVFKILREFL 161

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666  81 AKRFQDDLDVRYTAVSSFIFLRFFAPAILSPNLFQLTPHHTDPQTSRTLTLISKTIQTLGSLSkskSASFKESYMATFYE 160
Cdd:cd04519  162 AERFPEEPDEAYQAVSGFLFLRFICPAIVSPELFGLVPDEPSEQARRNLTLISKVLQSLANGV---EFGDKEPFMKPLND 238

                        170       180
                 ....*....|....*....|
gi 149057666 161 FFNEQKyaDAVKNFLDLISS 180
Cdd:cd04519  239 FIKSNK--PKLKQFLDELSS 256

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666   1 MKLAGMHYLHVTLKPTIEEICQSHKSCEIDPVKLKD------GENLENNMESLRQYVDRIFSVITKSGVSCPTVMCDIFF 74
Cdd:cd05137  110 MRRIGKEYLEKSIGDVIRKICEENKDCEVDPSRVKEsdsiekEEDLEENWENLISLTEEIWNSIYITSNDCPPELRKILK 189

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666  75 SLREAAAKRFQDDL-DVRYTAVSSFIFLRFFAPAILSPNLFQLTPHHTDPQTSRTLTLISKTIQTLGSLSKSksaSFKES 153
Cdd:cd05137  190 HIRAKVEDRYGDFLrTVTLNSVSGFLFLRFFCPAILNPKLFGLLKDHPRPRAQRTLTLIAKVLQNLANLTTF---GQKEP 266

                        170       180
                 ....*....|....*....|....*..
gi 149057666 154 YMATFYEFFNEQKyaDAVKNFLDLISS 180
Cdd:cd05137  267 WMEPMNEFLTTHR--EELKDYIDKITG 291

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666 196 KEGFMIKRAQGRKRFGMKNFKKRWFRLTNHEFTY-------QKSKGDQplcnIPIENILAVER-LEEESFRMKNMFQVIQ 267
Cdd:cd01238    1 LEGLLVKRSQGKKRFGPVNYKERWFVLTKSSLSYyegdgekRGKEKGS----IDLSKVRCVEEvKDEAFFERKYPFQVVY 76

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 149057666 268 PERALYIQANNCVEAKDWIDILTKVSQCNQKRLTVFHPSAYLNGHWLCCRASSDTAIGCTPCT 330
Cdd:cd01238   77 DDYTLYVFAPSEEDRDEWIAALRKVCRNNSNLHDKYHPGFWTGGKWSCCGQTSKSAPGCQPAF 139

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 149057666   2 KLAGMHYLHVTLKPTIEEICQSHKSCEIDPVKLKDgENLENNMESLRQYVDRIFSVITKSGVSCPTVMCDIFFSLREAAA 81
Cdd:cd05392   86 KSVGNKYLRKVLRPLLTEIVDNKDYFEVEKIKPDD-ENLEENADLLMKYAQMLLDSITDSVDQLPPSFRYICNTIYESVS 164

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666  82 KRFQDDLdvrYTAVSSFIFLRFFAPAILSPNLFQLTPHHTDPQTSRTLTLISKTIQTLGSLSKSksaSFKESYMATFYEF 161
Cdd:cd05392  165 KKFPDAA---LIAVGGFLFLRFICPAIVSPESENLLDPPPTPEARRSLILIAKVLQNIANGVLF---SLKEPYLESLNEF 238

                        170       180
                 ....*....|....*....|....*
gi 149057666 162 FNEQKyaDAVKNFLDLISSSGRRDP 186
Cdd:cd05392  239 LKKNS--DRIQQFLSEVSTIPPTDP 261

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 149057666   1 MKLAGMHYLHVTLKPTIEEICQSHKSCEIDPVKLKDGENLENNMESLRQYVDRIFSVITKSGVSCPTVMCDIFFSLREAA 80
Cdd:cd05391   89 MKATATPFVHHALKDTILKILESKQSCELNPSKLEKNEDVNTNLEHLLNILSELVEKIFMAAEILPPTLRYIYGCLQKSV 168

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666  81 AKRFQDDLDVRYTAVSSFIFLRFFAPAILSPNLFQLTPHHTDPQTSRTLTLISKTIQTLGSLSKSKSasfKESYMATFYE 160
Cdd:cd05391  169 QQKWPTNTTVRTRVVSGFVFLRLICPAILNPRMFNIISETPSPTAARTLTLVAKSLQNLANLVEFGA---KEPYMEGVNP 245

                        170       180       190
                 ....*....|....*....|....*....|..
gi 149057666 161 FFNEQKyaDAVKNFLDLISSSgRRDPKSIEQP 192
Cdd:cd05391  246 FIKKNK--ERMIMFLDELGNV-PELPDTTEHS 274

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666 193 ILLKEGFMIKR-AQGRKRFGMKNFKKRWFRLTNHEFTYQKSKGDQPLCNIPIENILAVERLEEESFRMKNMFQVIQPE-- 269
Cdd:cd13369   14 VTVKEGYLHKRkAEGVGLVTRFTFKKRYFWLSSETLSYSKSPDWQVRSSIPVQRICAVERVDENAFQQPNVMQVVTQDge 93

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 149057666 270 ---RALYIQANNCVEAKDWIDILTKVSQCNQKRLTVFHPSAYLNG 311
Cdd:cd13369   94 gqvHTTYIQCKNVNELNQWLSALRKVSLSNERMLPACHPGAFRSA 138

Dual Adaptor for Phosphotyrosine and 3-Phosphoinositides Pleckstrin homology (PH) domain; DAPP1 (also known as PHISH/3' phosphoinositide-interacting SH2 domain-containing protein or Bam32) plays a role in B-cell activation and has potential roles in T-cell and mast cell function. DAPP1 promotes B cell receptor (BCR) induced activation of Rho GTPases Rac1 and Cdc42, which feed into mitogen-activated protein kinases (MAPK) activation pathways and affect cytoskeletal rearrangement. DAPP1can also regulate BCR-induced activation of extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK). DAPP1 contains an N-terminal SH2 domain and a C-terminal pleckstrin homology (PH) domain with a single tyrosine phosphorylation site located centrally. DAPP1 binds strongly to both PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The PH domain is essential for plasma membrane recruitment of PI3K upon cell activation. 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 149057666 196 KEGFMIKRAQGRKrfgmkNFKKRWFRLTNHEFTYQKSKGD-QPLCNIPIENILAVERleEESFRMKNMFQVIQPERALYI 274
Cdd:cd10573    5 KEGYLTKLGGIVK-----NWKTRWFVLRRNELKYFKTRGDtKPIRVLDLRECSSVQR--DYSQGKVNCFCLVFPERTFYM 77

                         90
                 ....*....|....*
gi 149057666 275 QANNCVEAKDWIDIL 289
Cdd:cd10573   78 YANTEEEADEWVKLL 92

Ras-GTPase Activating Domain of GAPA; GAPA is an IQGAP-related protein and is predicted to bind to small GTPases, which are yet to be identified. IQGAP proteins are integral components of cytoskeletal regulation. Results from truncated GAPAs indicated that almost the entire region of GAPA homologous to IQGAP is required for cytokinesis in Dictyostelium. More members of the IQGAP family are emerging, and evidence suggests that there are both similarities and differences in their function.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666   5 GMHYLHVTLKPTIEEICqSHK--SCEIDPVK-----LKDGE-------NLENNMES-------------------LRQYV 51
Cdd:cd05132   67 GQSYLKTVLADRINDLI-SLKdlNLEINPLKvyeqmINDIEldtglpsNLPRGITPeeaaenpavqniieprlemLEEIT 145

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666  52 DRIFSVITKSGVSCPTVMCDIFFSLREAAAKRFQDDLD-VRYTAVSSFIFLRFFAPAILSPNLFQLTPHHTDPQTSRTLT 130
Cdd:cd05132  146 NSFLEAIINSLDEVPYGIRWICKQIRSLTRRKFPDASDeTICSLIGGFFLLRFINPAIVSPQAYMLVDGKPSDNTRRTLT 225

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*...
gi 149057666 131 LISKTIQTLGslskSKSASFKESYMATFYEFFNEQKyaDAVKNFLDLI 178
Cdd:cd05132  226 LIAKLLQNLA----NKPSYSKEPYMAPLQPFVEENK--ERLNKFLNDL 267

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666 196 KEGFMIKRaqgrKRFGMKNFKKRWFRLTNHEFTYQKSKGD---QPLCNIPIENILAVERLEEESfrMKNMFQVI-QPERA 271
Cdd:cd00821    1 KEGYLLKR----GGGGLKSWKKRWFVLFEGVLLYYKSKKDssyKPKGSIPLSGILEVEEVSPKE--RPHCFELVtPDGRT 74

                         90
                 ....*....|....*...
gi 149057666 272 LYIQANNCVEAKDWIDIL 289
Cdd:cd00821   75 YYLQADSEEERQEWLKAL 92

Fungal proteins Pleckstrin homology (PH) domain, repeat 1; The functions of these fungal proteins are unknown, but they all contain 2 PH domains. This cd represents the first PH repeat. 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 149057666 194 LLKEGFMIKRaqGRKRfgmKNFKKRWFRLTNHEFTYQK-SKGDQPLCNIPIENILAVERLEEEsfRMKNMFQVIQPERAL 272
Cdd:cd13298    6 VLKSGYLLKR--SRKT---KNWKKRWVVLRPCQLSYYKdEKEYKLRRVINLSELLAVAPLKDK--KRKNVFGIYTPSKNL 78

                         90       100
                 ....*....|....*....|..
gi 149057666 273 YIQANNCVEAKDWIDILTKVSQ 294
Cdd:cd13298   79 HFRATSEKDANEWVEALREEFR 100

Tandem PH-domain-containing proteins 1 and 2 Pleckstrin homology (PH) domain, C-terminal repeat; The binding of TAPP1 (also called PLEKHA1/pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 1) and TAPP2 (also called PLEKHA2) adaptors to PtdIns(3,4)P(2), but not PI(3,4, 5)P3, function as negative regulators of insulin and PI3K signalling pathways (i.e. TAPP/utrophin/syntrophin complex). TAPP1 and TAPP2 contain two sequential PH domains in which the C-terminal PH domain specifically binds PtdIns(3,4)P2 with high affinity. The N-terminal PH domain does not interact with any phosphoinositide tested. They also contain a C-terminal PDZ-binding motif that interacts with several PDZ-binding proteins, including PTPN13 (known previously as PTPL1 or FAP-1) as well as the scaffolding proteins MUPP1 (multiple PDZ-domain-containing protein 1), syntrophin and utrophin. 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 149057666 192 PILLKEGFMIKraQGRKrfgMKNFKKRWFRLTNHEFTYQKSKGD-QPLCNIPIENILAVERLEEESFRMK-NMFQVIQPE 269
Cdd:cd13271    6 RNVIKSGYCVK--QGAV---RKNWKRRFFILDDNTISYYKSETDkEPLRTIPLREVLKVHECLVKSLLMRdNLFEIITTS 80

                         90
                 ....*....|....*..
gi 149057666 270 RALYIQANNCVEAKDWI 286
Cdd:cd13271   81 RTFYIQADSPEEMHSWI 97

Tandem PH-domain-containing protein 2 Pleckstrin homology (PH) domain; The binding of TAPP2 (also called PLEKHA2) adaptors to PtdIns(3,4)P(2), but not PI(3,4, 5)P3, function as negative regulators of insulin and PI3K signalling pathways (i.e. TAPP/utrophin/syntrophin complex). TAPP2 contains two sequential PH domains in which the C-terminal PH domain specifically binds PtdIns(3,4)P2 with high affinity. The N-terminal PH domain does not interact with any phosphoinositide tested. They also contain a C-terminal PDZ-binding motif that interacts with several PDZ-binding proteins, including PTPN13 (known previously as PTPL1 or FAP-1) as well as the scaffolding proteins MUPP1 (multiple PDZ-domain-containing protein 1), syntrophin and utrophin. The members here are most sequence similar to TAPP2 proteins, but may not be actual TAPP2 proteins. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666 189 IEQPILLKEGFMIKRAQGRKRFgmknfKKRWFRLTNHEFTYQKS-KGDQPLCNIPIENILAVERLEEEsfRMKNMFQVIQ 267
Cdd:cd13255    1 MISEAVLKAGYLEKKGERRKTW-----KKRWFVLRPTKLAYYKNdKEYRLLRLIDLTDIHTCTEVQLK--KHDNTFGIVT 73

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 149057666 268 PERALYIQANNCVEAKDWIDILTKVSQCNQKRLTV 302
Cdd:cd13255   74 PARTFYVQADSKAEMESWISAINLARQALRATITP 108

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. 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 149057666 196 KEGFMIKRAqGRkrfgMKNFKKRWFRLTNHEFTYQKSKGD---QPLCNIPIENILAVERLEEesfrmKNMFQVIQPERAL 272
Cdd:cd13282    1 KAGYLTKLG-GK----VKTWKRRWFVLKNGELFYYKSPNDvirKPQGQIALDGSCEIARAEG-----AQTFEIVTEKRTY 70

                         90       100
                 ....*....|....*....|....*.
gi 149057666 273 YIQANNCVEAKDWIDILTKVSQCNQK 298
Cdd:cd13282   71 YLTADSENDLDEWIRVIQNVLRRQAS 96

Type 2 Diacylglycerol kinase Pleckstrin homology (PH) domain; DGK (also called DAGK) catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA) utilizing ATP as a source of the phosphate. In non-stimulated cells, DGK activity is low and DAG is used for glycerophospholipid biosynthesis. Upon receptor activation of the phosphoinositide pathway, DGK activity increases which drives the conversion of DAG to PA. DGK acts as a switch by terminating the signalling of one lipid while simultaneously activating signalling by another. There are 9 mammalian DGK isoforms all with conserved catalytic domains and two cysteine rich domains. These are further classified into 5 groups according to the presence of additional functional domains and substrate specificity: Type 1 - DGK-alpha, DGK-beta, DGK-gamma - contain EF-hand motifs and a recoverin homology domain; Type 2 - DGK-delta, DGK-eta, and DGK-kappa- contain a pleckstrin homology domain, two cysteine-rich zinc finger-like structures, and a separated catalytic region; Type 3 - DGK-epsilon - has specificity for arachidonate-containing DAG; Type 4 - DGK-zeta, DGK-iota- contain a MARCKS homology domain, ankyrin repeats, a C-terminal nuclear localization signal, and a PDZ-binding motif; Type 5 - DGK-theta - contains a third cysteine-rich domain, a pleckstrin homology domain and a proline rich region. The type 2 DGKs are present as part of this Metazoan DGK hierarchy. They have a N-terminal PH domain, two cysteine rich domains, followed by bipartite catalytic domains, and a C-terminal SAM domain. Their catalytic domains and perhaps other DGK catalytic domains may function as two independent units in a coordinated fashion. They may also require other motifs for maximal activity because several DGK catalytic domains have very little DAG kinase activity when expressed as isolated subunits. 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 149057666 195 LKEGFMIKRAQGRKRFgmknfKKRWFRLTNHEFTYQKSKGdqplCNIPIENILAVERLEEESFR-MKNMFQVIQPERALY 273
Cdd:cd13274    1 IKEGPLLKQTSSFQRW-----KRRYFKLKGRKLYYAKDSK----SLIFEEIDLSDASVAECSTKnVNNSFTVITPFRKLI 71

                         90       100
                 ....*....|....*....|.
gi 149057666 274 IQANNCVEAKDWIDILTKVSQ 294
Cdd:cd13274   72 LCAESRKEMEEWISALKTVQQ 92

Switch-associated protein-70 Pleckstrin homology (PH) domain; SWAP-70 (also called Differentially expressed in FDCP 6/DEF-6 or IRF4-binding protein) functions in cellular signal transduction pathways (in conjunction with Rac), regulates cell motility through actin rearrangement, and contributes to the transformation and invasion activity of mouse embryo fibroblasts. Metazoan SWAP-70 is found in B lymphocytes, mast cells, and in a variety of organs. Metazoan SWAP-70 contains an N-terminal EF-hand motif, a centrally located PH domain, and a C-terminal coiled-coil domain. The PH domain of Metazoan SWAP-70 contains a phosphoinositide-binding site and a nuclear localization signal (NLS), which localize SWAP-70 to the plasma membrane and nucleus, respectively. The NLS is a sequence of four Lys residues located at the N-terminus of the C-terminal a-helix; this is a unique characteristic of the Metazoan SWAP-70 PH domain. The SWAP-70 PH domain binds PtdIns(3,4,5)P3 and PtdIns(4,5)P2 embedded in lipid bilayer vesicles. There are additional plant SWAP70 proteins, but these are not included in this hierarchy. Rice SWAP70 (OsSWAP70) exhibits GEF activity toward the its Rho GTPase, OsRac1, and regulates chitin-induced production of reactive oxygen species and defense gene expression in rice. Arabidopsis SWAP70 (AtSWAP70) plays a role in both PAMP- and effector-triggered immunity. Plant SWAP70 contains both DH and PH domains, but their arrangement is the reverse of that in typical DH-PH-type Rho GEFs, wherein the DH domain is flanked by a C-terminal PH domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 149057666 195 LKEGFMIKRAqgrkrFGMKNFKKRWFRLTNHEFTYQKSKGDQPLC-NIPIENILAVERLEEESFRmKNMFQVIQPERALY 273
Cdd:cd13273    9 IKKGYLWKKG-----HLLPTWTERWFVLKPNSLSYYKSEDLKEKKgEIALDSNCCVESLPDREGK-KCRFLVKTPDKTYE 82

                         90
                 ....*....|...
gi 149057666 274 IQANNCVEAKDWI 286
Cdd:cd13273   83 LSASDHKTRQEWI 95