Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924 191 FIMKLVDIEEKEELDLQRALNSQAPPVKEGPLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIR 270
Cdd:cd13372     1 FITKLVDIEEEDELDLTRMLLLQAPMVKEGFLFIHRTKGKGPLMASSFKKLYFTLTKDALSFAKTPHSKKSSSISLAKIR 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924 271 AAEKVEEKSFGSSHIMQVIYADDVGRAQTVYLQCKCVNELNQWLSALRKASTNNRGLLRS 330
Cdd:cd13372    81 AAEKVEEKCFGSSNVMQIIYTDDAGQQETLYLQCKSVNELNQWLSALRKVCSNNTNLLSS 140

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924 191 FIMKLVDIEEKEELDLQRALNSQAPPVKEGPLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIR 270
Cdd:cd13372     1 FITKLVDIEEEDELDLTRMLLLQAPMVKEGFLFIHRTKGKGPLMASSFKKLYFTLTKDALSFAKTPHSKKSSSISLAKIR 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924 271 AAEKVEEKSFGSSHIMQVIYADDVGRAQTVYLQCKCVNELNQWLSALRKASTNNRGLLRS 330
Cdd:cd13372    81 AAEKVEEKCFGSSNVMQIIYTDDAGQQETLYLQCKSVNELNQWLSALRKVCSNNTNLLSS 140

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 1907164924   1 MESFLKVA-GMRYLHGILGPIIDRVFE-EKKYVELDPSKVEVK----------------DVGCSGLHRPQTEAEVLEQSA 62
Cdd:pfam00616  30 LETYNRRPrGQEYLKKVLGPLVRKIIEdEDLDLESDPRKIYESlinqeelktgrsdlprDVSPEEAIEDPEVRQIFEDNL 109

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924  63 QTLRAHLVALLSAICRSVRTCPAIIRATFRQLFRRVRERFPNAQHQNVpFIAVTSFLCLRFFSPAILSPKLFHLRERHAD 142
Cdd:pfam00616 110 QKLRELADEFLDAIYSSLNQLPYGIRYICKQLYELLEEKFPDASEEEI-LNAIGGFLFLRFFCPAIVNPDLFGLVDHQIS 188

                         170
                  ....*....|....*....
gi 1907164924 143 ARTSRTLLLLAKAVQNIGN 161
Cdd:pfam00616 189 PKQRRNLTLIAKVLQNLAN 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 1907164924  216 PVKEGPLFIhrtkgKGPLASSSFKKLYFSLTTEALSFAKTSSSKKST----FIKLASIRAAEKVEEKSFGSSHIMQVIYA 291
Cdd:smart00233   1 VIKEGWLYK-----KSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYkpkgSIDLSGCTVREAPDPDSSKKPHCFEIKTS 75

                           90       100       110
                   ....*....|....*....|....*....|
gi 1907164924  292 DDvgraQTVYLQCKCVNELNQWLSALRKAS 321
Cdd:smart00233  76 DR----KTLLLQAESEEEREKWVEALRKAI 101

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

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1907164924  324 NRGLLRSYHPGIFRGDKWSCCHQKDKTDQGCDKTH 358
Cdd:smart00107   1 NNNLLQKYHPSFWVDGKWLCCQQSEKNAPGCTPYE 35

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 1907164924   1 MESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVEVKDVGCSGLHRPQTEAEVLEQSAQTLRAHLVALLSAICRSV 80
Cdd:cd05135    89 MEQFMKVVGMPYLHEVLKPVINRIFEEKKYVELDPCKIDLNRTRRISFKGSLSEAQVRESSLELLQGYLGSIIDAIVGSV 168

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924  81 RTCPAIIRATFRQLFRRVRERFPNAQHQNVPFIAVTSFLCLRFFSPAILSPKLFHLRERHADARTSRTLLLLAKAVQNIG 160
Cdd:cd05135   169 DQCPPVMRVAFKQLHKRVEERFPEAEHQDVKYLAISGFLFLRFFAPAILTPKLFQLREQHADPRTSRTLLLLAKAVQSIG 248

                         170       180       190
                  ....*....|....*....|....*....|....*....
gi 1907164924 161 NMDTPVSRAKESWMEPLQPTVRQGVAQLKDFIMKLVDIE 199
Cdd:cd05135   249 NLGLQLGQGKEQWMAPLHPFILQSVARVKDFLDRLIDID 287

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 1907164924   1 MESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVEVKDVgcsglhrpqteaevLEQSAQTLRAHLVALLSAICRSV 80
Cdd:cd05128    84 MDEFMKLVGMQYLHETLKPVIDEIFSEKKSCEIDPSKLKDGEV--------------LETNLANLRGYVERVFKAITSSA 149

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924  81 RTCPAIIRATFRQLFRRVRERFPNAQhqNVPFIAVTSFLCLRFFSPAILSPKLFHLRERHADARTSRTLLLLAKAVQNIG 160
Cdd:cd05128   150 RRCPTLMCEIFSDLRESAAQRFPDNE--DVPYTAVSGFIFLRFFAPAILNPKLFGLREEHPDPQTARTLTLISKTIQTLG 227

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|..
gi 1907164924 161 NMDTPVS--RAKESWMEPLQ--PTVRQGVAQLKDFIMKLVDI 198
Cdd:cd05128   228 NLGSSSSglGVKEAYMSPLYerFTDEQHVDAVKKFLDRISSV 269

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924 218 KEGPLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIRAAEKVEEKSFGSSHIMQVIYADdvgra 297
Cdd:cd01244     1 KEGYLIKRAQGRKKKFGRKNFKKRYFRLTNEALSYSKSKGKQPLCSIPLEDILAVERVEEESFKMKNMFQIVQPD----- 75

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1907164924 298 QTVYLQCKCVNELNQWLSALRKASTNNRGLL 328
Cdd:cd01244    76 RTLYLQAKNVVELNEWLSALRKVCLCNPNRL 106

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 1907164924 207 QRALNSQAPPVKEGPLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIRAAEKVEEKSFGSSHIM 286
Cdd:cd13369     6 PRALFPPSVTVKEGYLHKRKAEGVGLVTRFTFKKRYFWLSSETLSYSKSPDWQVRSSIPVQRICAVERVDENAFQQPNVM 85

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1907164924 287 QVIYADDVGRAQTVYLQCKCVNELNQWLSALRKASTNNRGLLRSYHPGIFRG 338
Cdd:cd13369    86 QVVTQDGEGQVHTTYIQCKNVNELNQWLSALRKVSLSNERMLPACHPGAFRS 137

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924   1 MESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKvevkdvgcsglhrpqTEAEVLEQSAQTLRAHLVALLSAICRSV 80
Cdd:cd04519    79 LDQYMKLVGQEYLKETLSPLIREILESKESCEIDTKL---------------PVGEDLEENLENLLELVNKLVDRILSSL 143

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924  81 RTCPAIIRATFRQLFRRVRERFPNAQHqnVPFIAVTSFLCLRFFSPAILSPKLFHLRERHADARTSRTLLLLAKAVQNIG 160
Cdd:cd04519   144 DRLPPELRYVFKILREFLAERFPEEPD--EAYQAVSGFLFLRFICPAIVSPELFGLVPDEPSEQARRNLTLISKVLQSLA 221

                         170       180       190
                  ....*....|....*....|....*....|....*..
gi 1907164924 161 NMDTPVSraKESWMEPLQPTVRQGVAQLKDFIMKLVD 197
Cdd:cd04519   222 NGVEFGD--KEPFMKPLNDFIKSNKPKLKQFLDELSS 256

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 1907164924   1 MESFLKVAGMRYLHGILGPIIDRVFEEKKYVELDPSKVEvkdvgcsglhrpqtEAEVLEQSAQTLRAHLVALLSAICRSV 80
Cdd:cd05394    84 LDEMMKIVGKHYLKVTLKPVLDEICESPKPCEIDPIKLK--------------EGDNVENNKENLRYYVDKVFFSIVKSS 149

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924  81 RTCPAIIRATFRQLFRRVRERFPNAQHqnVPFIAVTSFLCLRFFSPAILSPKLFHLRERHADARTSRTLLLLAKAVQNIG 160
Cdd:cd05394   150 MSCPTLMCDVFRSLRHLAVKRFPNDPH--VQYSAVSSFVFLRFFAVAVVSPHTFQLRPHHPDAQTSRTLTLISKTIQTLG 227

                         170
                  ....*....|....*...
gi 1907164924 161 NMDT----PVSRAKESWM 174
Cdd:cd05394   228 SWGSlsksKLSSFKETFM 245

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 1907164924 218 KEGpLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKST---FIKLASIRAAEKVE-EKSFGSSHIMQVIYADD 293
Cdd:cd01238     1 LEG-LLVKRSQGKKRFGPVNYKERWFVLTKSSLSYYEGDGEKRGKekgSIDLSKVRCVEEVKdEAFFERKYPFQVVYDDY 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1907164924 294 vgraqTVYLQCKCVNELNQWLSALRKASTNNRGLLRSYHPGIFRGDKWSCCHQKDKTDQGCDKT 357
Cdd:cd01238    80 -----TLYVFAPSEEDRDEWIAALRKVCRNNSNLHDKYHPGFWTGGKWSCCGQTSKSAPGCQPA 138

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 1907164924   4 FLKVAGMRYLHGILGPIIDRVFEEKKYVELDpskvevkdvgcsglhRPQTEAEVLEQSAQTLRAHLVALLSAICRSVRTC 83
Cdd:cd05392    84 YAKSVGNKYLRKVLRPLLTEIVDNKDYFEVE---------------KIKPDDENLEENADLLMKYAQMLLDSITDSVDQL 148

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924  84 PAIIRATFRQLFRRVRERFPNAqhqnvPFIAVTSFLCLRFFSPAILSPKLFHLRERHADARTSRTLLLLAKAVQNIGNmd 163
Cdd:cd05392   149 PPSFRYICNTIYESVSKKFPDA-----ALIAVGGFLFLRFICPAIVSPESENLLDPPPTPEARRSLILIAKVLQNIAN-- 221

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|..
gi 1907164924 164 TPVSRAKESWMEPLQPTVRQGVAQLKDFIMKLVDIEEKEELD 205
Cdd:cd05392   222 GVLFSLKEPYLESLNEFLKKNSDRIQQFLSEVSTIPPTDPIF 263

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 1907164924 217 VKEGPLFiHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIRAAEKVEEKSFGSSHIMQVIYADdvgr 296
Cdd:cd13370    17 LKEGEMH-KRAQGRTRIGKKNFKKRWFCLTSRELTYHKQKGKEAIFTIPVKNILAVEKLEESAFNKKNMFQVIHSE---- 91

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1907164924 297 aQTVYLQCKCVNELNQWLSALRKASTNNRGLLRSYHPGIFRG 338
Cdd:cd13370    92 -KPLYVQANNCVEANEWIEVLSRVSRCNQKRLSFYHPSAYLG 132

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 1907164924  216 PVKEGPLFIhrtkgKGPLASSSFKKLYFSLTTEALSFAKTSSSKKST----FIKLASIRAAEKVEEKSFGSSHIMQVIYA 291
Cdd:smart00233   1 VIKEGWLYK-----KSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYkpkgSIDLSGCTVREAPDPDSSKKPHCFEIKTS 75

                           90       100       110
                   ....*....|....*....|....*....|
gi 1907164924  292 DDvgraQTVYLQCKCVNELNQWLSALRKAS 321
Cdd:smart00233  76 DR----KTLLLQAESEEEREKWVEALRKAI 101

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 1907164924 217 VKEGpLFIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKSTFIKLASIRAAEKVEEKSFGSSHIMQVIYADdvgr 296
Cdd:cd13371    17 LKEG-FMIKRAQGRKRFGMKNFKKRWFRLTNHEFTYHKSKGDHPLCSIPIENILAVERLEEESFKMKNMFQVIQPE---- 91

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1907164924 297 aQTVYLQCKCVNELNQWLSALRKASTNNRGLLRSY 331
Cdd:cd13371    92 -RALYIQANNCVEAKDWIDILTKVSQCNKKRLTVY 125

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924 216 PVKEGPLFIhrtkgKGPLASSSFKKLYFSLTTEALSFAKTSSSKKST----FIKLASIRAAEKVEEKSFGSSHIMQVIYa 291
Cdd:pfam00169   1 VVKEGWLLK-----KGGGKKKSWKKRYFVLFDGSLLYYKDDKSGKSKepkgSISLSGCEVVEVVASDSPKRKFCFELRT- 74

                          90       100       110
                  ....*....|....*....|....*....|
gi 1907164924 292 DDVGRAQTVYLQCKCVNELNQWLSALRKAS 321
Cdd:pfam00169  75 GERTGKRTYLLQAESEEERKDWIKAIQSAI 104

Ras-GTPase Activating Domain of IQ motif containing GTPase activating proteins; This family represents IQ motif containing GTPase activating protein (IQGAP) which associated with the Ras GTP-binding protein. A primary function of IQGAP proteins is to modulate cytoskeletal architecture. There are three known IQGAP family members: IQGAP1, IQGAP2 and IQGAP3. Human IQGAP1 and IQGAP2 share 62% identity. IQGAPs are multi-domain molecules having a calponin-homology (CH) domain which binds F-actin, IQGAP-specific repeats, a single WW domain, four IQ motifs that mediate interactions with calmodulin, and a RasGAP related domain that binds active Rho family GTPases. IQGAP is an essential regulator of cytoskeletal function. IQGAP1 negatively regulates Ras family GTPases by stimulating their intrinsic GTPase activity, the protein actually lacks GAP activity. Both IQGAP1 and IQGAP2 specifically bind to Cdc42 and Rac1, but not to RhoA. Despite of their similarities to part of the sequence of RasGAP, neither IQGAP1 nor IQGAP2 interacts with Ras. IQGAP3, only present in mammals, regulates the organization of the cytoskeleton under the regulation of Rac1 and Cdc42 in neuronal cells. The depletion of IQGAP3 is shown to impair neurite or axon outgrowth in neuronal cells with disorganized cytoskeleton.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924  12 YLHGILGPIIDRVFEEKK-YVELDPSKV--------EVKdvgcSGL--HRPQT--------EAEV---LEQSAQTLRAHL 69
Cdd:cd05127    55 YLRELLGPVVKEILDDDDlDLETDPVDIykawinqeESR----TGEpsKLPYDvtreqalkDPEVrkrLIEHLEKLRAIT 130

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924  70 VALLSAICRSVRTCPAIIRATFRQLFRRVRERFPNAqHQNVPFIAVTSFLCLRFFSPAILSPKLFHLRERHADARTS--- 146
Cdd:cd05127   131 DKFLTAITESLDKMPYGMRYIAKVLKEALREKFPDA-PEEEILKIVGNLLYYRYMNPAIVAPEAFDIIDLSVGGQLSplq 209

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907164924 147 -RTLLLLAKAVQNI--GNM---DTPvsrakesWMEPLQPTVRQGVAQLKDFIMKLVDIEEKEE 203
Cdd:cd05127   210 rRNLGSIAKVLQQAasGKLfggENP-------YLSPLNPYISESHEKFKKFFLEACTVPEAEE 265

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

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1907164924  324 NRGLLRSYHPGIFRGDKWSCCHQKDKTDQGCDKTH 358
Cdd:smart00107   1 NNNLLQKYHPSFWVDGKWLCCQQSEKNAPGCTPYE 35

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924 200 EKEELDLqralnSQAPPVKEGPlfIHRTKGKGPLASSSFKKLYFSLTTEALSFAKTSSSKKST----FIKLASIRAA-EK 274
Cdd:cd13258     5 EKELAAL-----SSQPAEKEGK--IAERQMGGPKKSEVFKERWFKLKGNLLFYFRTNEFGDCSepigAIVLENCRVQmEE 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1907164924 275 VEEKSFGSShimqVIYADDVGRAQtvYLQCKCVNELNQWLSALRKAS 321
Cdd:cd13258    78 ITEKPFAFS----IVFNDEPEKKY--IFSCRSEEQCEQWIEALRQAS 118

Ras-GTPase Activating Domain of IQ motif containing GTPase activating protein 3; This family represents the IQ motif containing GTPase activating protein 3 (IQGAP3), which associates with Ras GTP-binding proteins. A primary function of IQGAP proteins is to modulate cytoskeletal architecture. There are three known IQGAP family members: IQGAP1, IQGAP2 and IQGAP3. Human IQGAP1 and IQGAP2 share 62% identity. IQGAPs are multi-domain molecules having a calponin-homology (CH) domain which binds F-actin, IQGAP-specific repeats, a single WW domain, four IQ motifs that mediate interactions with calmodulin, and a RasGAP related domain that binds active Rho family GTPases. IQGAP is an essential regulator of cytoskeletal function. IQGAP1 negatively regulates Ras family GTPases by stimulating their intrinsic GTPase activity, the protein actually lacks GAP activity. Both IQGAP1 and IQGAP2 specifically bind to Cdc42 and Rac1, but not to RhoA. Despite of their similarities to part of the sequence of RasGAP, neither IQGAP1 nor IQGAP2 interacts with Ras. IQGAP3, only present in mammals, regulates the organization of the cytoskeleton under the regulation of Rac1 and Cdc42 in neuronal cells. The depletion of IQGAP3 is shown to impair neurite or axon outgrowth in neuronal cells with disorganized cytoskeleton.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924   9 GMRYLHGILGPIIDRVFEEKKY-VELDP--------SKVEVKDVGCSGLHRPQTEAEVL---------EQSAQTLRAHLV 70
Cdd:cd12207    62 GQNALRHILGPVVQDVLQDKGLsIRTDPvqiykawiNQTETQSGCRSSLPYEVSPEQALshpevqrrlDIAIRNLLAVTD 141

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907164924  71 ALLSAICRSVRTCPAIIRATFRQLFRRVRERFPNAQHQNVPFIaVTSFLCLRFFSPAILSPKLFHLRE------RHADAR 144
Cdd:cd12207   142 KFLSAITSSVDKIPYGMRYVAKVLRDSLQEKFPGASEDEVYKV-VGNLLYYRFMNPAVVAPDGFDIVDcsaggaLQPEQR 220

                         170
                  ....*....|....
gi 1907164924 145 tsRTLLLLAKAVQN 158
Cdd:cd12207   221 --RMLGSVAKVLQH 232