Ral GEF with PH domain and SH3 binding motif 1 and 2 Pleckstrin homology (PH) domain; RalGPS1 (also called Ral GEF with PH domain and SH3 binding motif 1;RALGEF2/ Ral guanine nucleotide exchange factor 2; RalA exchange factor RalGPS1; Ral guanine nucleotide exchange factor RalGPS1A2; ras-specific guanine nucleotide-releasing factor RalGPS1) and RalGPS2 (also called Ral GEF with PH domain and SH3 binding motif 2; Ral-A exchange factor RalGPS2; ras-specific guanine nucleotide-releasing factor RalGPS22). They activate small GTPase Ral proteins such as RalA and RalB by stimulating the exchange of Ral bound GDP to GTP, thereby regulating various downstream cellular processes. Structurally they contain an N-terminal Cdc25-like catalytic domain, followed by a PXXP motif and a C-terminal PH domain. The Cdc25-like catalytic domain interacts with Ral and its PH domain ensures the correct membrane localization. Its PXXP motif is thought to interact with the SH3 domain of Grb2. 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 1720399096 354 TMEGPLRRKTLLKEGRKPALSSWTRYWVVLSGATLLYYGAKSLRGTDRKHYKSTPGKKVSIVGWMVQLPDDPEHPDIFQL 433
Cdd:cd13310     1 TMQGCLRRKTVLKEGRKPTVSSWQRYWVQLWGTSLVYYAPKSLKGTERSDFKSEPCKIVSISGWMVVLGDDPEHPDSFQL 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1720399096 434 NNPDKGNVYKFQTGSRFHAILWHKHLDDACKSSRPQ 469
Cdd:cd13310    81 TDPEKGNVYKFRAGSRSNALLWLKHLKDACKGNRPP 116

Ral GEF with PH domain and SH3 binding motif 1 and 2 Pleckstrin homology (PH) domain; RalGPS1 (also called Ral GEF with PH domain and SH3 binding motif 1;RALGEF2/ Ral guanine nucleotide exchange factor 2; RalA exchange factor RalGPS1; Ral guanine nucleotide exchange factor RalGPS1A2; ras-specific guanine nucleotide-releasing factor RalGPS1) and RalGPS2 (also called Ral GEF with PH domain and SH3 binding motif 2; Ral-A exchange factor RalGPS2; ras-specific guanine nucleotide-releasing factor RalGPS22). They activate small GTPase Ral proteins such as RalA and RalB by stimulating the exchange of Ral bound GDP to GTP, thereby regulating various downstream cellular processes. Structurally they contain an N-terminal Cdc25-like catalytic domain, followed by a PXXP motif and a C-terminal PH domain. The Cdc25-like catalytic domain interacts with Ral and its PH domain ensures the correct membrane localization. Its PXXP motif is thought to interact with the SH3 domain of Grb2. 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 1720399096 354 TMEGPLRRKTLLKEGRKPALSSWTRYWVVLSGATLLYYGAKSLRGTDRKHYKSTPGKKVSIVGWMVQLPDDPEHPDIFQL 433
Cdd:cd13310     1 TMQGCLRRKTVLKEGRKPTVSSWQRYWVQLWGTSLVYYAPKSLKGTERSDFKSEPCKIVSISGWMVVLGDDPEHPDSFQL 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1720399096 434 NNPDKGNVYKFQTGSRFHAILWHKHLDDACKSSRPQ 469
Cdd:cd13310    81 TDPEKGNVYKFRAGSRSNALLWLKHLKDACKGNRPP 116

Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. Guanine-nucleotide-exchange factors (GEFs) positively regulate these GTP-binding proteins in response to a variety of signals. GEFs catalyze the dissociation of GDP from the inactive GTP-binding proteins. GTP can then bind and induce structural changes that allow interaction with effectors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720399096  21 QITLMDIPVFKAIQPEELASCGWSKK-EKHSLAPNVVAFTRRFNQVSFWVVREILTAQTLKIRAEILSHFVKIAKKLLEL 99
Cdd:cd00155    12 QLTLLDFELFRKIEPFELLGSLWSKKdKNIHLSPNLERFIERFNNLSNWVASEILLCTNPKKRARLLSKFIQVAKHCREL 91

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720399096 100 NNLHSLMSVVSALQSAPIFRLTKTWALLNRKDKTTFEKLDYLMSKEDNYKRTRDYIRSLK-MVPSIPYLGIYLLDLIYID 178
Cdd:cd00155    92 NNFNSLMAIVSALSSSPISRLKKTWEVLSSKLKKLFEELEELVDPSRNFKNYRKLLKSVGpNPPCVPFLGVYLKDLTFLH 171

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1720399096 179 SAYPasGSIMENEQRSNQMNNILRIIADLQV--SCSYDhLTTLPHVQKYLKSVRYIEELqkfvEDDNYKLSLR 249
Cdd:cd00155   172 EGNP--DFLEGNLVNFEKRRKIAEILREIRQlqSNSYE-LNRDEDILAFLWKLLELILN----EDELYELSLE 237

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720399096 353 PTMEGPLRRKTllkegrKPALSSWTRYWVVLSGATLLYYGAKSlRGTDRKHYKSTPGKKVSIVgwMVQLPDDPEHPDIFQ 432
Cdd:pfam00169   1 VVKEGWLLKKG------GGKKKSWKKRYFVLFDGSLLYYKDDK-SGKSKEPKGSISLSGCEVV--EVVASDSPKRKFCFE 71

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1720399096 433 L--NNPDKGNVYKFQTGSRFHAILWHKHLDDACK 464
Cdd:pfam00169  72 LrtGERTGKRTYLLQAESEEERKDWIKAIQSAIR 105

Ral GEF with PH domain and SH3 binding motif 1 and 2 Pleckstrin homology (PH) domain; RalGPS1 (also called Ral GEF with PH domain and SH3 binding motif 1;RALGEF2/ Ral guanine nucleotide exchange factor 2; RalA exchange factor RalGPS1; Ral guanine nucleotide exchange factor RalGPS1A2; ras-specific guanine nucleotide-releasing factor RalGPS1) and RalGPS2 (also called Ral GEF with PH domain and SH3 binding motif 2; Ral-A exchange factor RalGPS2; ras-specific guanine nucleotide-releasing factor RalGPS22). They activate small GTPase Ral proteins such as RalA and RalB by stimulating the exchange of Ral bound GDP to GTP, thereby regulating various downstream cellular processes. Structurally they contain an N-terminal Cdc25-like catalytic domain, followed by a PXXP motif and a C-terminal PH domain. The Cdc25-like catalytic domain interacts with Ral and its PH domain ensures the correct membrane localization. Its PXXP motif is thought to interact with the SH3 domain of Grb2. 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 1720399096 354 TMEGPLRRKTLLKEGRKPALSSWTRYWVVLSGATLLYYGAKSLRGTDRKHYKSTPGKKVSIVGWMVQLPDDPEHPDIFQL 433
Cdd:cd13310     1 TMQGCLRRKTVLKEGRKPTVSSWQRYWVQLWGTSLVYYAPKSLKGTERSDFKSEPCKIVSISGWMVVLGDDPEHPDSFQL 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1720399096 434 NNPDKGNVYKFQTGSRFHAILWHKHLDDACKSSRPQ 469
Cdd:cd13310    81 TDPEKGNVYKFRAGSRSNALLWLKHLKDACKGNRPP 116

Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. Guanine-nucleotide-exchange factors (GEFs) positively regulate these GTP-binding proteins in response to a variety of signals. GEFs catalyze the dissociation of GDP from the inactive GTP-binding proteins. GTP can then bind and induce structural changes that allow interaction with effectors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720399096  21 QITLMDIPVFKAIQPEELASCGWSKK-EKHSLAPNVVAFTRRFNQVSFWVVREILTAQTLKIRAEILSHFVKIAKKLLEL 99
Cdd:cd00155    12 QLTLLDFELFRKIEPFELLGSLWSKKdKNIHLSPNLERFIERFNNLSNWVASEILLCTNPKKRARLLSKFIQVAKHCREL 91

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720399096 100 NNLHSLMSVVSALQSAPIFRLTKTWALLNRKDKTTFEKLDYLMSKEDNYKRTRDYIRSLK-MVPSIPYLGIYLLDLIYID 178
Cdd:cd00155    92 NNFNSLMAIVSALSSSPISRLKKTWEVLSSKLKKLFEELEELVDPSRNFKNYRKLLKSVGpNPPCVPFLGVYLKDLTFLH 171

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1720399096 179 SAYPasGSIMENEQRSNQMNNILRIIADLQV--SCSYDhLTTLPHVQKYLKSVRYIEELqkfvEDDNYKLSLR 249
Cdd:cd00155   172 EGNP--DFLEGNLVNFEKRRKIAEILREIRQlqSNSYE-LNRDEDILAFLWKLLELILN----EDELYELSLE 237

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720399096 353 PTMEGPLRRKTllkegrKPALSSWTRYWVVLSGATLLYYGAKSlRGTDRKHYKSTPGKKVSIVgwMVQLPDDPEHPDIFQ 432
Cdd:pfam00169   1 VVKEGWLLKKG------GGKKKSWKKRYFVLFDGSLLYYKDDK-SGKSKEPKGSISLSGCEVV--EVVASDSPKRKFCFE 71

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1720399096 433 L--NNPDKGNVYKFQTGSRFHAILWHKHLDDACK 464
Cdd:pfam00169  72 LrtGERTGKRTYLLQAESEEERKDWIKAIQSAIR 105

T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, N-terminal domain; Tiam1 activates Rac GTPases to induce membrane ruffling and cell motility while Tiam2 (also called STEF (SIF (still life) and Tiam1 like-exchange factor) contributes to neurite growth. Tiam1/2 are Dbl-family of GEFs that possess a Dbl(DH) domain with a PH domain in tandem. DH-PH domain catalyzes the GDP/GTP exchange reaction in the GTPase cycle and facillitating the switch between inactive GDP-bound and active GTP-bound states. Tiam1/2 possess two PH domains, which are often referred to as PHn and PHc domains. The DH-PH tandem domain is made up of the PHc domain while the PHn is part of a novel N-terminal PHCCEx domain which is made up of the PHn domain, a coiled coil region(CC), and an extra region (Ex). PHCCEx mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. The PH domain resembles the beta-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. CC and Ex form a positively charged surface for protein binding. There are 2 motifs in Tiam1/2-interacting proteins that bind to the PHCCEx domain: Motif-I in CD44, ephrinBs, and the NMDA receptor and Motif-II in Par3 and JIP2.Neither of these fall in the PHn 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 1720399096 364 LLKEGRKPALSS---WTRYWVVLSGATLLYYGAKSLRGTDRkhyKSTPGKKVSIVGWMVQLPddPEHP---DIFQLNNpD 437
Cdd:cd01230    16 VHKKNKKVELATrrkWKKYWVCLKGCTLLFYECDERSGIDE---NSEPKHALFVEGSIVQAV--PEHPkkdFVFCLSN-S 89

                          90       100
                  ....*....|....*....|....*...
gi 1720399096 438 KGNVYKFQTGSRFHAILWHKHLDDACKS 465
Cdd:cd01230    90 FGDAYLFQATSQTELENWVTAIHSACAS 117

Src kinase-associated phosphoprotein homolog and Skap 2 Pleckstrin homology (PH) domain; Adaptor protein Skap-hom, a homolog of Skap55, which interacts with actin and with ADAP (adhesion and degranulation promoting adapter protein) undergoes tyrosine phosphorylation in response to plating of bone marrow-derived macrophages on fibronectin. Skap-hom has an N-terminal coiled-coil conformation that is involved in homodimer formation, a central PH domain and a C-terminal SH3 domain that associates with ADAP. The Skap-hom PH domain regulates intracellular targeting; its interaction with the DM domain inhibits Skap-hom actin-based ruffles in macrophages and its binding to 3'-phosphoinositides reverses this autoinhibition. The Skap-hom PH domain binds PI[3,4]P2 and PI[3,4,5]P3, but not to PI[3]P, PI[5]P, or PI[4,5]P2. Skap2 is a downstream target of Heat shock transcription factor 4 (HSF4) and functions in the regulation of actin reorganization during lens differentiation. It is thought that SKAP2 anchors the complex of tyrosine kinase adaptor protein 2 (NCK20/focal adhesion to fibroblast growth factor receptors at the lamellipodium in lens epithelial cells. Skap2 has an N-terminal coiled-coil conformation which interacts with the SH2 domain of NCK2, a central PH domain and a C-terminal SH3 domain that associates with ADAP (adhesion and degranulation promoting adapter protein)/FYB (the Fyn binding protein). Skap2 PH domain binds to membrane lipids. Skap adaptor proteins couple receptors to cytoskeletal rearrangements. Src kinase-associated phosphoprotein of 55 kDa (Skap55)/Src kinase-associated phosphoprotein 1 (Skap1), Skap2, and Skap-hom have an N-terminal coiled-coil conformation, a central PH domain and a C-terminal SH3 domain. Their PH domains bind 3'-phosphoinositides as well as directly affecting targets such as in Skap55 where it directly affecting integrin regulation by ADAP and NF-kappaB activation or in Skap-hom where the dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch that controls ruffle formation. 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 1720399096 374 SSWTRYWVVLSGATLLYYGAKSlrgtdRKHYKStpgkKVSIVGWMVQLPD----DPEHPDIFQLNNPDKgNVYKFQTGSR 449
Cdd:cd13381    19 FEWQKRWCALSNSVFYYYGSDK-----DKQQKG----EFAIDGYDVKMNNtlrkDAKKDCCFEICAPDK-RVYQFTAASP 88

                          90
                  ....*....|....*
gi 1720399096 450 FHAILWHKHLDDACK 464
Cdd:cd13381    89 KEAEEWVQQIKFILQ 103

Myosin phosphatase-RhoA Interacting Protein Pleckstrin homology (PH) domain; M-RIP is proposed to play a role in myosin phosphatase regulation by RhoA. M-RIP contains 2 PH domains followed by a Rho binding domain (Rho-BD), and a C-terminal myosin binding subunit (MBS) binding domain (MBS-BD). The amino terminus of M-RIP with its adjacent PH domains and polyproline motifs mediates binding to both actin and Galpha. M-RIP brings RhoA and MBS into close proximity where M-RIP can target RhoA to the myosin phosphatase complex to regulate the myosin phosphorylation state. M-RIP does this via its C-terminal coiled-coil domain which interacts with the MBS leucine zipper domain of myosin phosphatase, while its Rho-BD, directly binds RhoA in a nucleotide-independent manner. 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
                  ....*....|....*....|....*....
gi 1720399096 364 LLKEGRKPalSSWTRYWVVLSGATLLYYG 392
Cdd:cd13275     5 LMKQGSRQ--GEWSKHWFVLRGAALKYYR 31