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 2462541425  451 QCCNEFIMEGPLTRIGA---KHERHIFLFDGLMISCKPNHGQTRLPGySSAEYRLKEKFVMRKIQICDKEDTCEHKHAFE 527
Cdd:cd01261      1 QCCNEFIMEGTLGKVGSgkrKTERHAFLFDGLLLLCKSNRRRTSTGG-PKPEYRLKEKFFIRKVEINDLEDTEELKNAFE 79

                           90       100       110
                   ....*....|....*....|....*....|
gi 2462541425  528 LVSKDENSIIFAAKSAEEKNNWMAALISLH 557
Cdd:cd01261     80 IVPRDQPSVILFAKSAEEKNNWMAALVMLN 109

Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif; A subset of guanine nucleotide exchange factor for Ras-like small GTPases appear to possess this domain N-terminal to the RasGef (Cdc25-like) domain. The recent crystal structureof Sos shows that this domain is alpha-helical and plays a "purely structural role" (Nature 394, 337-343).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   609 GIPIIKGGTVVKLIERLTYHMY-ADPNFVRTFLTTYRSFCKPQELLSLLIERFEIPEPEPTdadklaiekgeqpisadlk 687
Cdd:smart00229    1 DGGLIKGGTLEALIEHLTEAFDkADPSFVETFLLTYRSFITTQELLQLLLYRYNAIPPESW------------------- 61

                            90       100       110       120       130       140
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462541425   688 RFRKEYVQPVQLRILNVFRHWVEHHFYDFERDLELLERLESFISSVRGKAMKKWVESIAKIIRRKK 753
Cdd:smart00229   62 VEEKVNPRRVKNRVLNILRTWVENYWEDFEDDPKLISFLLEFLELVDDEKYPGLVTSLLNLLRRLS 127

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; 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. Improved coverage.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   254 IAEERQYLRELNMIIKVFREAFLSDRKLFKPSDIEKIFSNISDIHELTVKLLGLIEDTVEMTDesSPHPLAGSCFEDLAE 333
Cdd:smart00325    6 LQTERNYVRDLKLLVEVFLKPLKKELKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWD--DSVERIGDVFLKLEE 83

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   334 eqAFDPYETLSQDIlsPEFHEHFNKLMARPAVALHFQQ---------------------------------LKACSEEQE 380
Cdd:smart00325   84 --FFKIYSEYCSNH--PDALELLKKLKKNPRFQKFLKEiesspqcrrltleslllkpvqrltkyplllkelLKHTPEDHE 159

                           170       180
                    ....*....|....*....|.
gi 2462541425   381 DRECLNQAITALMNLQGSMDR 401
Cdd:smart00325  160 DREDLKKALKAIKELANQVNE 180

Guanine nucleotide exchange factor for Ras-like small GTPases;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   788 LMTLHPIEIARQLTLLESDLYRKVQPSELVGSVWTKEDKEINSP-NLLKMIRHTTNLTLWFEKCIVEAENFEERVAVLSR 866
Cdd:smart00147    1 LLLLDPKELAEQLTLLDFELFRKIDPSELLGSVWGKRSKKSPSPlNLEAFIRRFNEVSNWVATEILKQTTPKDRAELLSK 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   867 IIEILQVFQDLNNFNGVLEIVSAVNSVSVYRLDHTFEALQERKRKILDEAVEL--SQDHFKKYLVKLKSIN-PPCVPFFG 943
Cdd:smart00147   81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEKLPSKYKKLFEELEELlsPERNYKNYREALSSCNlPPCIPFLG 160

                           170       180       190       200       210       220       230       240
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   944 IYLTNILKTEEGNNDFLKKKgkdLINFSKRRKVAEITGEIQQYQNQPYCLRIEPDMRRFFENLNPMGSASEkeftDYLFN 1023
Cdd:smart00147  161 VLLKDLTFIDEGNPDFLENG---LVNFEKRRQIAEILREIRQLQSQPYNLRPNRSDIQSLLQQLLDHLDEE----EELYQ 233

                    ....*....
gi 2462541425  1024 KSLEIEPRN 1032
Cdd:smart00147  234 LSLKIEPRV 242

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 2462541425  451 QCCNEFIMEGPLTRIGA---KHERHIFLFDGLMISCKPNHGQTRLPGySSAEYRLKEKFVMRKIQICDKEDTCEHKHAFE 527
Cdd:cd01261      1 QCCNEFIMEGTLGKVGSgkrKTERHAFLFDGLLLLCKSNRRRTSTGG-PKPEYRLKEKFFIRKVEINDLEDTEELKNAFE 79

                           90       100       110
                   ....*....|....*....|....*....|
gi 2462541425  528 LVSKDENSIIFAAKSAEEKNNWMAALISLH 557
Cdd:cd01261     80 IVPRDQPSVILFAKSAEEKNNWMAALVMLN 109

Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif; A subset of guanine nucleotide exchange factor for Ras-like small GTPases appear to possess this domain N-terminal to the RasGef (Cdc25-like) domain. The recent crystal structureof Sos shows that this domain is alpha-helical and plays a "purely structural role" (Nature 394, 337-343).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   609 GIPIIKGGTVVKLIERLTYHMY-ADPNFVRTFLTTYRSFCKPQELLSLLIERFEIPEPEPTdadklaiekgeqpisadlk 687
Cdd:smart00229    1 DGGLIKGGTLEALIEHLTEAFDkADPSFVETFLLTYRSFITTQELLQLLLYRYNAIPPESW------------------- 61

                            90       100       110       120       130       140
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462541425   688 RFRKEYVQPVQLRILNVFRHWVEHHFYDFERDLELLERLESFISSVRGKAMKKWVESIAKIIRRKK 753
Cdd:smart00229   62 VEEKVNPRRVKNRVLNILRTWVENYWEDFEDDPKLISFLLEFLELVDDEKYPGLVTSLLNLLRRLS 127

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 2462541425  617 TVVKLIERLTYHM-YADPNFVRTFLTTYRSFCKPQELLSLLIERFEIPEPEPTDAdklaiekgeqpisadlKRFRKEYVQ 695
Cdd:cd06224      1 TLEALIEHLTSTFdMPDPSFVSTFLLTYRSFTTPTELLEKLIERYEIAPPENLEY----------------NDWDKKKSK 64

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 2462541425  696 PVQLRILNVFRHWVEHHFYDFERDLELLERLESFISSVR--GKAMKKWVESIAKIIRR 751
Cdd:cd06224     65 PIRLRVLNVLRTWVENYPYDFFDDEELLELLEEFLNRLVqeGALLQELKKLLRKLLKL 122

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; 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. Improved coverage.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   254 IAEERQYLRELNMIIKVFREAFLSDRKLFKPSDIEKIFSNISDIHELTVKLLGLIEDTVEMTDesSPHPLAGSCFEDLAE 333
Cdd:smart00325    6 LQTERNYVRDLKLLVEVFLKPLKKELKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWD--DSVERIGDVFLKLEE 83

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   334 eqAFDPYETLSQDIlsPEFHEHFNKLMARPAVALHFQQ---------------------------------LKACSEEQE 380
Cdd:smart00325   84 --FFKIYSEYCSNH--PDALELLKKLKKNPRFQKFLKEiesspqcrrltleslllkpvqrltkyplllkelLKHTPEDHE 159

                           170       180
                    ....*....|....*....|.
gi 2462541425   381 DRECLNQAITALMNLQGSMDR 401
Cdd:smart00325  160 DREDLKKALKAIKELANQVNE 180

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 2462541425   456 FIMEGPLTRIGAK-----HERHIFLFDGLMISCKPNHGQTRlpgyssaeYRLKEKFVMRKIQI--CDKEDTCEHKHAFEL 528
Cdd:smart00233    1 VIKEGWLYKKSGGgkkswKKRYFVLFNSTLLYYKSKKDKKS--------YKPKGSIDLSGCTVreAPDPDSSKKPHCFEI 72

                            90       100       110
                    ....*....|....*....|....*....|
gi 2462541425   529 VSKDENSIIFAAKSAEEKNNWMAALISLHY 558
Cdd:smart00233   73 KTSDRKTLLLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425  457 IMEGPLTRIGAK-----HERHIFLFDGLMISCKPnhgqtrlpGYSSAEYRLKEKFVMRKIQICD--KEDTCEHKHAFELV 529
Cdd:pfam00169    2 VKEGWLLKKGGGkkkswKKRYFVLFDGSLLYYKD--------DKSGKSKEPKGSISLSGCEVVEvvASDSPKRKFCFELR 73

                           90       100       110
                   ....*....|....*....|....*....|..
gi 2462541425  530 SKD---ENSIIFAAKSAEEKNNWMAALISLHY 558
Cdd:pfam00169   74 TGErtgKRTYLLQAESEEERKDWIKAIQSAIR 105

Histone H2A [Chromatin structure and dynamics];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425  131 KWAIADAQSAIEKRKRRNPLLLPVDKIHPSLKEVLG-YKVDYHVSLYIVAVLEYISADILKLAGNYVFNIRHYEISQQDI 209
Cdd:COG5262      6 KGGKAADARVSQSRSAKAGLIFPVGRVKRLLKKGNYrMRIGAGAPVYLAAVLEYLAAEILELAGNAARDNKKKRIIPRHL 85

                           90
                   ....*....|
gi 2462541425  210 KVSMCADKVL 219
Cdd:COG5262     86 QLAIRNDEEL 95

Guanine nucleotide exchange factor for Ras-like small GTPases;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   788 LMTLHPIEIARQLTLLESDLYRKVQPSELVGSVWTKEDKEINSP-NLLKMIRHTTNLTLWFEKCIVEAENFEERVAVLSR 866
Cdd:smart00147    1 LLLLDPKELAEQLTLLDFELFRKIDPSELLGSVWGKRSKKSPSPlNLEAFIRRFNEVSNWVATEILKQTTPKDRAELLSK 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   867 IIEILQVFQDLNNFNGVLEIVSAVNSVSVYRLDHTFEALQERKRKILDEAVEL--SQDHFKKYLVKLKSIN-PPCVPFFG 943
Cdd:smart00147   81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEKLPSKYKKLFEELEELlsPERNYKNYREALSSCNlPPCIPFLG 160

                           170       180       190       200       210       220       230       240
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   944 IYLTNILKTEEGNNDFLKKKgkdLINFSKRRKVAEITGEIQQYQNQPYCLRIEPDMRRFFENLNPMGSASEkeftDYLFN 1023
Cdd:smart00147  161 VLLKDLTFIDEGNPDFLENG---LVNFEKRRQIAEILREIRQLQSQPYNLRPNRSDIQSLLQQLLDHLDEE----EELYQ 233

                    ....*....
gi 2462541425  1024 KSLEIEPRN 1032
Cdd:smart00147  234 LSLKIEPRV 242

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 2462541425  451 QCCNEFIMEGPLTRIGA---KHERHIFLFDGLMISCKPNHGQTRLPGySSAEYRLKEKFVMRKIQICDKEDTCEHKHAFE 527
Cdd:cd01261      1 QCCNEFIMEGTLGKVGSgkrKTERHAFLFDGLLLLCKSNRRRTSTGG-PKPEYRLKEKFFIRKVEINDLEDTEELKNAFE 79

                           90       100       110
                   ....*....|....*....|....*....|
gi 2462541425  528 LVSKDENSIIFAAKSAEEKNNWMAALISLH 557
Cdd:cd01261     80 IVPRDQPSVILFAKSAEEKNNWMAALVMLN 109

Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif; A subset of guanine nucleotide exchange factor for Ras-like small GTPases appear to possess this domain N-terminal to the RasGef (Cdc25-like) domain. The recent crystal structureof Sos shows that this domain is alpha-helical and plays a "purely structural role" (Nature 394, 337-343).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   609 GIPIIKGGTVVKLIERLTYHMY-ADPNFVRTFLTTYRSFCKPQELLSLLIERFEIPEPEPTdadklaiekgeqpisadlk 687
Cdd:smart00229    1 DGGLIKGGTLEALIEHLTEAFDkADPSFVETFLLTYRSFITTQELLQLLLYRYNAIPPESW------------------- 61

                            90       100       110       120       130       140
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462541425   688 RFRKEYVQPVQLRILNVFRHWVEHHFYDFERDLELLERLESFISSVRGKAMKKWVESIAKIIRRKK 753
Cdd:smart00229   62 VEEKVNPRRVKNRVLNILRTWVENYWEDFEDDPKLISFLLEFLELVDDEKYPGLVTSLLNLLRRLS 127

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 2462541425  617 TVVKLIERLTYHM-YADPNFVRTFLTTYRSFCKPQELLSLLIERFEIPEPEPTDAdklaiekgeqpisadlKRFRKEYVQ 695
Cdd:cd06224      1 TLEALIEHLTSTFdMPDPSFVSTFLLTYRSFTTPTELLEKLIERYEIAPPENLEY----------------NDWDKKKSK 64

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 2462541425  696 PVQLRILNVFRHWVEHHFYDFERDLELLERLESFISSVR--GKAMKKWVESIAKIIRR 751
Cdd:cd06224     65 PIRLRVLNVLRTWVENYPYDFFDDEELLELLEEFLNRLVqeGALLQELKKLLRKLLKL 122

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; 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. Improved coverage.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   254 IAEERQYLRELNMIIKVFREAFLSDRKLFKPSDIEKIFSNISDIHELTVKLLGLIEDTVEMTDesSPHPLAGSCFEDLAE 333
Cdd:smart00325    6 LQTERNYVRDLKLLVEVFLKPLKKELKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWD--DSVERIGDVFLKLEE 83

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425   334 eqAFDPYETLSQDIlsPEFHEHFNKLMARPAVALHFQQ---------------------------------LKACSEEQE 380
Cdd:smart00325   84 --FFKIYSEYCSNH--PDALELLKKLKKNPRFQKFLKEiesspqcrrltleslllkpvqrltkyplllkelLKHTPEDHE 159

                           170       180
                    ....*....|....*....|.
gi 2462541425   381 DRECLNQAITALMNLQGSMDR 401
Cdd:smart00325  160 DREDLKKALKAIKELANQVNE 180

Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. 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 2462541425  431 IKKMNEIQKNIDGWEGKDIGQCCNEFIMEGPLTRIGAKH--ERHIFLFDGLMISCKPNHGQTRLPGYssaeyrlKEKFVM 508
Cdd:cd01224      4 LEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKISAGRaqERTFFLFDHQLVYCKKDLLRRKNYIY-------KGRIDT 76

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|...
gi 2462541425  509 RKIQICDKEDTCEH------KHAFELVSKDEN-SIIFAAKSAEEKNNWMAALI 554
Cdd:cd01224     77 DNMEIEDLPDGKDDesgvtvKNAWKIYNASKNkWYVLCAKSAEEKQRWLEAFA 129

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 2462541425  257 ERQYLRELNMIIKVFREaFLSDRKLFKPSDIEKIFSNISDIHELTVKLlgLIEdtvEMTDESSPHPLAGSCFEDLAEEqa 336
Cdd:pfam00621    9 ERSYVRDLEILVEVFLP-PNSKPLSESEEEIKTIFSNIEEIYELHRQL--LLE---ELLKEWISIQRIGDIFLKFAPG-- 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425  337 FDPYETL------SQDILS------PEFHEHFNKLMARPAVA-------------------LHFQQL-KACSEEQEDREC 384
Cdd:pfam00621   81 FKVYSTYcsnypkALKLLKkllkknPKFRAFLEELEANPECRgldlnsflikpvqriprypLLLKELlKHTPPDHPDYED 160

                          170
                   ....*....|....*.
gi 2462541425  385 LNQAITALMNLQGSMD 400
Cdd:pfam00621  161 LKKALEAIKEVAKQIN 176

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425  458 MEGPLTRIGAK-----HERHIFLFDGLMISCKPNHGQTrlpgyssaeYRLKEKFVMRKIQICDKEDTCEHKHAFELVSKD 532
Cdd:cd00821      1 KEGYLLKRGGGglkswKKRWFVLFEGVLLYYKSKKDSS---------YKPKGSIPLSGILEVEEVSPKERPHCFELVTPD 71

                           90       100
                   ....*....|....*....|.
gi 2462541425  533 ENSIIFAAKSAEEKNNWMAAL 553
Cdd:cd00821     72 GRTYYLQADSEEERQEWLKAL 92

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 2462541425  459 EGPLTRIGAKH----ERHIFLFDGLMISCKPnhgQTRLPGyssAEYRLKEKFVMRKIQICDKEDTcEHKHAFeLVSKDEN 534
Cdd:cd13328      2 EGQILKLSAKNgtpqPRYLFLFNDMLLYCVP---KLSLVG---QKFSVRNRLDVAGMKVREPVNE-NYPHTF-KISGKER 73

                           90
                   ....*....|....*....
gi 2462541425  535 SIIFAAKSAEEKNNWMAAL 553
Cdd:cd13328     74 SLELQASSAEEKDEWIQAI 92

histone-fold domain found in histone H2A and similar proteins; Histone H2A is the core component of the nucleosome, which wraps and compacts DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462541425  142 EKRKRRNPLLLPVDKIHPSLKEvlgYKVDYHVS----LYIVAVLEYISADILKLAGNYVFNIRHYEISQQDIKVSMCADK 217
Cdd:cd00074      1 QSRSKRAGLQFPVGRIHRLLKK---GTYAKRVGagapVYLAAVLEYLTAEILELAGNAARDNKKKRITPRHIQLAIRNDE 77

                   ....*.
gi 2462541425  218 VLMDMF 223
Cdd:cd00074     78 ELNKLF 83

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 2462541425  456 FIMEGPLT---RIGAKhERHIFLFDGLMI--SCKPNHGQtrlpgyssaeYRLKEKFVMRKIQICDKEDTCEHKHAFELVS 530
Cdd:cd01218     30 LVGEGVLTkvcRKKPK-PRQFFLFNDILVygSIVINKKK----------YNKQRIIPLEDVKIEDLEDTGELKNGWQIIS 98

                           90       100
                   ....*....|....*....|...
gi 2462541425  531 KDENSIIFAAkSAEEKNNWMAAL 553
Cdd:cd01218     99 PKKSFVVYAA-TATEKSEWMDHI 120

Histone 2A;

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 2462541425   144 RKRRNPLLLPVDKIHPSLKE-VLGYKVDYHVSLYIVAVLEYISADILKLAGN 194
Cdd:smart00414    2 RSARAGLQFPVGRIHRLLRKgTYAKRVGAGAPVYLAAVLEYLTAEVLELAGN 53

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 2, 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. Not much is known about FGD2. FGD1 is the best characterized member of the group with mutations here leading to 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 2462541425  456 FIMEGPLTRIGAKH----ERHIFLFDGLMISCKPNHGQTRlpgyssAEYRLKEKFVMRKIQICDKEDTcEHKHAFeLVSK 531
Cdd:cd13386      1 LLKEGPVLKISFRNnnpkERYLFLFNNMLLYCVPKVIQVG------AKFQVHMRIDVDGMKVRELNDA-EFPHSF-LVSG 72

                           90       100
                   ....*....|....*....|.
gi 2462541425  532 DENSIIFAAKSAEEKNNWMAA 552
Cdd:cd13386     73 KQRTLELQARSQEEMEAWIQA 93