Son of Sevenless (SOS) Pleckstrin homology (PH) domain; SOS is a Ras guanine nucleotide exchange factor. SOS is thought to transmit signals from activated receptor tyrosine kinases to the Ras signaling pathway. SOS contains a histone domain, Dbl-homology (DH), a PH domain, Rem domain, Cdc25 domain, and a Grb2 binding domain. The SOS PH domain binds to phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidic acid (PA). SOS is dependent on Ras binding to the allosteric site via its histone domain for both a lower level of activity (Ras GDP) and maximal activity (Ras GTP). The DH domain blocks the allosteric Ras binding site in SOS. The PH domain is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS. The C-terminal proline-rich domain of SOS binds to the adapter protein Grb2 which localizes the Sos protein to the plasma membrane and diminishes the negative effect of the C-terminal domain on the guanine nucleotide exchange activity of the CDC25-homology domain of SOS. 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 564356217  266 QCCNEFIMEGPLTRIGA---KHERHIFLFDGLMISCKPNHCQTRLPGySSAEYRLKEKFVMRKIQICDKEDACEYKHAFE 342
Cdd:cd01261     1 QCCNEFIMEGTLGKVGSgkrKTERHAFLFDGLLLLCKSNRRRTSTGG-PKPEYRLKEKFFIRKVEINDLEDTEELKNAFE 79

                          90       100       110
                  ....*....|....*....|....*....|
gi 564356217  343 LVSKDENSVIFAAKSAEEKNNWMAALISLH 372
Cdd:cd01261    80 IVPRDQPSVILFAKSAEEKNNWMAALVMLN 109

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217   28 YYDLVRTEIAEERQYLRELNMIIKVFREAFLSDKKLFKSSEIEKIFSNISDIHELTVKLLGLIEDTVEMTDesSPHPLAG 107
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWD--KSGPRIG 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217  108 SCFEDLAEeqAFDPYETLSQDIlaPEFNDHFSKLMarpAVALHFQSIADGF-KEAVRYVLPRLMLVPVYHCWHYFELLKQ 186
Cdd:cd00160    79 DVFLKLAP--FFKIYSEYCSNH--PDALELLKKLK---KFNKFFQEFLEKAeSECGRLKLESLLLKPVQRLTKYPLLLKE 151

                         170       180       190
                  ....*....|....*....|....*....|
gi 564356217  187 LKACSEE-QEDRECLNQAITALMNLQGSMD 215
Cdd:cd00160   152 LLKHTPDgHEDREDLKKALEAIKEVASQVN 181

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 564356217  603 LMTLHPIEIARQLTLLESDLYRRVQPSELVGSVWTKEDKEI-NSPNLLKMIRHTTNLTLWFEKCIVEAENFEERVAVLSR 681
Cdd:cd00155     1 FLSLDPKELAEQLTLLDFELFRKIEPFELLGSLWSKKDKNIhLSPNLERFIERFNNLSNWVASEILLCTNPKKRARLLSK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217  682 IVEILQVFQDLNNFNGVLEIVSAVNSVSVYRLDHTFEALQERKRRVLDDAVEL--SQDHFKKYLVKLKSI--NPPCVPFF 757
Cdd:cd00155    81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEVLSSKLKKLFEELEELvdPSRNFKNYRKLLKSVgpNPPCVPFL 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217  758 GIYLTNILKTEEGNSDFLKRKgkdLINFSKRRKVAEITGEIQQYQNQPYCLRTEPEMRRFFENLNPmgllsEKEFTDYLF 837
Cdd:cd00155   161 GVYLKDLTFLHEGNPDFLEGN---LVNFEKRRKIAEILREIRQLQSNSYELNRDEDILAFLWKLLE-----LILNEDELY 232

                  ....*
gi 564356217  838 NKSHE 842
Cdd:cd00155   233 ELSLE 237

Son of Sevenless (SOS) Pleckstrin homology (PH) domain; SOS is a Ras guanine nucleotide exchange factor. SOS is thought to transmit signals from activated receptor tyrosine kinases to the Ras signaling pathway. SOS contains a histone domain, Dbl-homology (DH), a PH domain, Rem domain, Cdc25 domain, and a Grb2 binding domain. The SOS PH domain binds to phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidic acid (PA). SOS is dependent on Ras binding to the allosteric site via its histone domain for both a lower level of activity (Ras GDP) and maximal activity (Ras GTP). The DH domain blocks the allosteric Ras binding site in SOS. The PH domain is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS. The C-terminal proline-rich domain of SOS binds to the adapter protein Grb2 which localizes the Sos protein to the plasma membrane and diminishes the negative effect of the C-terminal domain on the guanine nucleotide exchange activity of the CDC25-homology domain of SOS. 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 564356217  266 QCCNEFIMEGPLTRIGA---KHERHIFLFDGLMISCKPNHCQTRLPGySSAEYRLKEKFVMRKIQICDKEDACEYKHAFE 342
Cdd:cd01261     1 QCCNEFIMEGTLGKVGSgkrKTERHAFLFDGLLLLCKSNRRRTSTGG-PKPEYRLKEKFFIRKVEINDLEDTEELKNAFE 79

                          90       100       110
                  ....*....|....*....|....*....|
gi 564356217  343 LVSKDENSVIFAAKSAEEKNNWMAALISLH 372
Cdd:cd01261    80 IVPRDQPSVILFAKSAEEKNNWMAALVMLN 109

Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately N-terminal to the RasGef (Cdc25-like) domain. REM contacts the GTPase and is assumed to participate in the catalytic activity of the exchange factor. Proteins with the REM domain include Sos1 and Sos2, which relay signals from tyrosine-kinase mediated signalling to Ras, RasGRP1-4, RasGRF1,2, CNrasGEF, and RAP-specific nucleotide exchange factors, to name a few.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217  432 TVVKLIERLTYHM-YADPNFVRTFLTTYRSFCKPQELLSLLIERFEIPDPEPTEAdklalekgeqpisadlKRFRKEYVQ 510
Cdd:cd06224     1 TLEALIEHLTSTFdMPDPSFVSTFLLTYRSFTTPTELLEKLIERYEIAPPENLEY----------------NDWDKKKSK 64

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 564356217  511 PVQLRVLNVFRHWVEHHFYDFERDLELLERLEAFISSVR--GKAMKKWVESIAKIIKR 566
Cdd:cd06224    65 PIRLRVLNVLRTWVENYPYDFFDDEELLELLEEFLNRLVqeGALLQELKKLLRKLLKL 122

RasGEF N-terminal motif; A subset of guanine nucleotide exchange factor for Ras-like small GTPases appear to possess this motif/domain N-terminal to the RasGef (Cdc25-like) domain.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217   427 IIKGGTVVKLIERLTYHMYA-DPNFVRTFLTTYRSFCKPQELLSLLIERFEIPDPEPTEADKLALEKGEQPIsadlkrfr 505
Cdd:pfam00618    1 QVKAGTLEKLVEYLTSTRIMlDDSFLSTFLLTYRSFTTPAELLELLIERYNIPPPLDLSSDSYWISKKTLPI-------- 72

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 564356217   506 keyvqpvQLRVLNVFRHWVEHHFYDFERDLELLERLEAF 544
Cdd:pfam00618   73 -------RIRVLSVLRHWVENYFSDFNDDPVLLSRLEKF 104

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217    39 ERQYLRELNMIIKVFREaflSDKKLFKSS--EIEKIFSNISDIHELTVKLLglIEdtvEMTDESSPHPLAGSCFEDLAEE 116
Cdd:pfam00621    9 ERSYVRDLEILVEVFLP---PNSKPLSESeeEIKTIFSNIEEIYELHRQLL--LE---ELLKEWISIQRIGDIFLKFAPG 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217   117 qaFDPYETLSQDIlaPEFNDHFSKLMARPAVALHFQSIADGFKEAVRYVLPRLMLVPVYHCWHYFELLKQL-KACSEEQE 195
Cdd:pfam00621   81 --FKVYSTYCSNY--PKALKLLKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELlKHTPPDHP 156

                          170       180
                   ....*....|....*....|
gi 564356217   196 DRECLNQAITALMNLQGSMD 215
Cdd:pfam00621  157 DYEDLKKALEAIKEVAKQIN 176

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217   272 IMEGPLTRIGAK-----HERHIFLFDGLMISCKPnhcqtrlpGYSSAEYRLKEKFVMRKIQICD--KEDACEYKHAFELV 344
Cdd:pfam00169    2 VKEGWLLKKGGGkkkswKKRYFVLFDGSLLYYKD--------DKSGKSKEPKGSISLSGCEVVEvvASDSPKRKFCFELR 73

                           90       100       110
                   ....*....|....*....|....*....|..
gi 564356217   345 SKD---ENSVIFAAKSAEEKNNWMAALISLHY 373
Cdd:pfam00169   74 TGErtgKRTYLLQAESEEERKDWIKAIQSAIR 105

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 564356217  603 LMTLHPIEIARQLTLLESDLYRRVQPSELVGSVWTKEDKEI-NSPNLLKMIRHTTNLTLWFEKCIVEAENFEERVAVLSR 681
Cdd:cd00155     1 FLSLDPKELAEQLTLLDFELFRKIEPFELLGSLWSKKDKNIhLSPNLERFIERFNNLSNWVASEILLCTNPKKRARLLSK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217  682 IVEILQVFQDLNNFNGVLEIVSAVNSVSVYRLDHTFEALQERKRRVLDDAVEL--SQDHFKKYLVKLKSI--NPPCVPFF 757
Cdd:cd00155    81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEVLSSKLKKLFEELEELvdPSRNFKNYRKLLKSVgpNPPCVPFL 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217  758 GIYLTNILKTEEGNSDFLKRKgkdLINFSKRRKVAEITGEIQQYQNQPYCLRTEPEMRRFFENLNPmgllsEKEFTDYLF 837
Cdd:cd00155   161 GVYLKDLTFLHEGNPDFLEGN---LVNFEKRRKIAEILREIRQLQSNSYELNRDEDILAFLWKLLE-----LILNEDELY 232

                  ....*
gi 564356217  838 NKSHE 842
Cdd:cd00155   233 ELSLE 237

Son of Sevenless (SOS) Pleckstrin homology (PH) domain; SOS is a Ras guanine nucleotide exchange factor. SOS is thought to transmit signals from activated receptor tyrosine kinases to the Ras signaling pathway. SOS contains a histone domain, Dbl-homology (DH), a PH domain, Rem domain, Cdc25 domain, and a Grb2 binding domain. The SOS PH domain binds to phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidic acid (PA). SOS is dependent on Ras binding to the allosteric site via its histone domain for both a lower level of activity (Ras GDP) and maximal activity (Ras GTP). The DH domain blocks the allosteric Ras binding site in SOS. The PH domain is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS. The C-terminal proline-rich domain of SOS binds to the adapter protein Grb2 which localizes the Sos protein to the plasma membrane and diminishes the negative effect of the C-terminal domain on the guanine nucleotide exchange activity of the CDC25-homology domain of SOS. 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 564356217  266 QCCNEFIMEGPLTRIGA---KHERHIFLFDGLMISCKPNHCQTRLPGySSAEYRLKEKFVMRKIQICDKEDACEYKHAFE 342
Cdd:cd01261     1 QCCNEFIMEGTLGKVGSgkrKTERHAFLFDGLLLLCKSNRRRTSTGG-PKPEYRLKEKFFIRKVEINDLEDTEELKNAFE 79

                          90       100       110
                  ....*....|....*....|....*....|
gi 564356217  343 LVSKDENSVIFAAKSAEEKNNWMAALISLH 372
Cdd:cd01261    80 IVPRDQPSVILFAKSAEEKNNWMAALVMLN 109

Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately N-terminal to the RasGef (Cdc25-like) domain. REM contacts the GTPase and is assumed to participate in the catalytic activity of the exchange factor. Proteins with the REM domain include Sos1 and Sos2, which relay signals from tyrosine-kinase mediated signalling to Ras, RasGRP1-4, RasGRF1,2, CNrasGEF, and RAP-specific nucleotide exchange factors, to name a few.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217  432 TVVKLIERLTYHM-YADPNFVRTFLTTYRSFCKPQELLSLLIERFEIPDPEPTEAdklalekgeqpisadlKRFRKEYVQ 510
Cdd:cd06224     1 TLEALIEHLTSTFdMPDPSFVSTFLLTYRSFTTPTELLEKLIERYEIAPPENLEY----------------NDWDKKKSK 64

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 564356217  511 PVQLRVLNVFRHWVEHHFYDFERDLELLERLEAFISSVR--GKAMKKWVESIAKIIKR 566
Cdd:cd06224    65 PIRLRVLNVLRTWVENYPYDFFDDEELLELLEEFLNRLVqeGALLQELKKLLRKLLKL 122

RasGEF N-terminal motif; A subset of guanine nucleotide exchange factor for Ras-like small GTPases appear to possess this motif/domain N-terminal to the RasGef (Cdc25-like) domain.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217   427 IIKGGTVVKLIERLTYHMYA-DPNFVRTFLTTYRSFCKPQELLSLLIERFEIPDPEPTEADKLALEKGEQPIsadlkrfr 505
Cdd:pfam00618    1 QVKAGTLEKLVEYLTSTRIMlDDSFLSTFLLTYRSFTTPAELLELLIERYNIPPPLDLSSDSYWISKKTLPI-------- 72

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 564356217   506 keyvqpvQLRVLNVFRHWVEHHFYDFERDLELLERLEAF 544
Cdd:pfam00618   73 -------RIRVLSVLRHWVENYFSDFNDDPVLLSRLEKF 104

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217    39 ERQYLRELNMIIKVFREaflSDKKLFKSS--EIEKIFSNISDIHELTVKLLglIEdtvEMTDESSPHPLAGSCFEDLAEE 116
Cdd:pfam00621    9 ERSYVRDLEILVEVFLP---PNSKPLSESeeEIKTIFSNIEEIYELHRQLL--LE---ELLKEWISIQRIGDIFLKFAPG 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217   117 qaFDPYETLSQDIlaPEFNDHFSKLMARPAVALHFQSIADGFKEAVRYVLPRLMLVPVYHCWHYFELLKQL-KACSEEQE 195
Cdd:pfam00621   81 --FKVYSTYCSNY--PKALKLLKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELlKHTPPDHP 156

                          170       180
                   ....*....|....*....|
gi 564356217   196 DRECLNQAITALMNLQGSMD 215
Cdd:pfam00621  157 DYEDLKKALEAIKEVAKQIN 176

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 564356217    271 FIMEGPLTRIGAK-----HERHIFLFDGLMISCKPNHcqtrlpgySSAEYRLKEKFVMRKIQI--CDKEDACEYKHAFEL 343
Cdd:smart00233    1 VIKEGWLYKKSGGgkkswKKRYFVLFNSTLLYYKSKK--------DKKSYKPKGSIDLSGCTVreAPDPDSSKKPHCFEI 72

                            90       100       110
                    ....*....|....*....|....*....|
gi 564356217    344 VSKDENSVIFAAKSAEEKNNWMAALISLHY 373
Cdd:smart00233   73 KTSDRKTLLLQAESEEEREKWVEALRKAIA 102

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia family proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). 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 564356217  274 EGPLTRIGAKH----ERHIFLFDGLMISCKPnhcQTRLPGyssAEYRLKEKFVMRKIQICDKEDAcEYKHAFeLVSKDEN 349
Cdd:cd13328     2 EGQILKLSAKNgtpqPRYLFLFNDMLLYCVP---KLSLVG---QKFSVRNRLDVAGMKVREPVNE-NYPHTF-KISGKER 73

                          90
                  ....*....|....*....
gi 564356217  350 SVIFAAKSAEEKNNWMAAL 368
Cdd:cd13328    74 SLELQASSAEEKDEWIQAI 92

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 1-4 and similar proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. They play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway. FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. 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 564356217  272 IMEGPLTRIGAK----HERHIFLFDGLMISCKPnhcQTRLPGyssAEYRLKEKFVMRKIQICDKEDAcEYKHAFElVSKD 347
Cdd:cd13388     2 IKEGKILKISARngdtQERYLFLFNDMLLYCSP---RLRLIG---QKYKVRARFDVDGMQVLEGDNL-ETPHTFY-VRGK 73

                          90       100
                  ....*....|....*....|.
gi 564356217  348 ENSVIFAAKSAEEKNNWMAAL 368
Cdd:cd13388    74 QRSLELQASTQEEKAEWVDAI 94

Vav pleckstrin homology (PH) domain; Vav acts as a guanosine nucleotide exchange factor (GEF) for Rho/Rac proteins. They control processes including T cell activation, phagocytosis, and migration of cells. The Vav subgroup of Dbl GEFs consists of three family members (Vav1, Vav2, and Vav3) in mammals. Vav1 is preferentially expressed in the hematopoietic system, while Vav2 and Vav3 are described by broader expression patterns. Mammalian Vav proteins consist of a calponin homology (CH) domain, an acidic region, a catalytic Dbl homology (DH) domain, a PH domain, a zinc finger cysteine rich domain (C1/CRD), and an SH2 domain, flanked by two SH3 domains. In invertebrates such as Drosophila and C. elegans, Vav is missing the N-terminal SH3 domain. The DH domain is involved in RhoGTPase recognition and selectivity and stimulates the reorganization of the switch regions for GDP/GTP exchange. The PH domain is implicated in directing membrane localization, allosteric regulation of guanine nucleotide exchange activity, and as a phospholipid- dependent regulator of GEF activity. Vavs bind RhoGTPases including Rac1, RhoA, RhoG, and Cdc42, while other members of the GEF family are specific for a single RhoGTPase. This promiscuity is thought to be a result of its CRD. 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.polarized. PH domains also have diverse functions. They are often involved in targeting proteins to the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. 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 kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564356217  282 AKHERHIFLFDGLMISCKpnhcqtRLPGYSsaeYRLKE-----KFVMRKIQICDKEDAC-EYKHAFELVSKDENSVI-FA 354
Cdd:cd01223    34 KKKDRYAFLFDKVLLICK------SLRGDQ---YEYKEiinlsEYRIEDDPSRRTLKRDkRWSYQFLLVHKQGKTAYtLY 104

                          90
                  ....*....|....
gi 564356217  355 AKSAEEKNNWMAAL 368
Cdd:cd01223   105 AKTEELKKKWMEAI 118

Phafin2 (also called EAPF, FLJ13187, ZFYVE18 or PLEKHF2) Pleckstrin Homology (PH) domain; Phafin2 is differentially expressed in the liver cancer cell and regulates the structure and function of the endosomes through Rab5-dependent processes. Phafin2 modulates the cell's response to extracellular stimulation by modulating the receptor density on the cell surface. Phafin2 contains a PH domain and a FYVE 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 564356217  271 FIMEGPLT---RIGAKhERHIFLFD-----GLMISCKPNhcqtrlpgyssaeYRLKEKFVMRKIQICDKEDACEYKHAFE 342
Cdd:cd01218    30 LVGEGVLTkvcRKKPK-PRQFFLFNdilvyGSIVINKKK-------------YNKQRIIPLEDVKIEDLEDTGELKNGWQ 95

                          90       100
                  ....*....|....*....|....*.
gi 564356217  343 LVSKDENSVIFAAkSAEEKNNWMAAL 368
Cdd:cd01218    96 IISPKKSFVVYAA-TATEKSEWMDHI 120

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 4, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. 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 564356217  271 FIMEGPLTRIGAKH----ERHIFLFDGLMISCKPnhcQTRLPGyssAEYRLKEKFVMRKIQICDKEDAcEYKHAFElVSK 346
Cdd:cd15791     1 LIKEGQILKLAARNtsaqERYLFLFNNMLLYCVP---KFSLVG---SKYTVRTRIGIDGMKVVETQNE-DYPHTFQ-VSG 72

                          90       100
                  ....*....|....*....|..
gi 564356217  347 DENSVIFAAKSAEEKNNWMAAL 368
Cdd:cd15791    73 KERTLELQASSEQDKEEWIKAL 94

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 3, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. However, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells and while FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. They also reciprocally regulated cell motility in inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration while FGD3 inhibited it. FGD1 and FGD3 therefore play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP). 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 564356217  271 FIMEGPLTRIGAKH----ERHIFLFDGLMISCKPnhcQTRLPGyssAEYRLKEKFVMRKIQICD--KEDAceyKHAFELV 344
Cdd:cd13387     1 LIKEGHIQKLSAKNgtaqDRYLYLFNSMVLYCVP---KLRLMG---QKFSVREKIDIAGMQVQEivKQNV---PHTFTIT 71

                          90       100
                  ....*....|....*....|.
gi 564356217  345 SKdENSVIFAAKSAEEKNNWM 365
Cdd:cd13387    72 GK-KRSLELQARTEEEKKEWI 91

p63RhoGEF pleckstrin homology (PH) domain, repeat 2; The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric G protein, Galphaq and linking Galphaq-coupled receptors (GPCRs) to the activation of RhoA. The Dbl(DH) and PH domains of p63RhoGEF interact with the effector-binding site and the C-terminal region of Galphaq and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of Galphaq effectors that appear to activate RhoA both in vitro and in intact cells. Dbs is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Trio is a multidomain signaling protein that contains two RhoGEF(DH)-PH domains in tandem. 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 564356217  285 ERHIFLFDGLMISCKPnhcQTRLPGYSSAEYRLKEKFVMRKIQICDKEDACEYKhaFELVSKDEN----SVIFAAKSAEE 360
Cdd:cd13241    38 ERRVFLFEQIIIFSEI---LGKKTQFSNPGYIYKNHIKVNKMSLEENVDGDPLR--FALKSRDPNnpseTFILQAASPEV 112

                          90       100
                  ....*....|....*....|...
gi 564356217  361 KNNWMaalislhyrSTLDRMLDS 383
Cdd:cd13241   113 RQEWV---------DTINQILDT 126