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
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1907195722 212 QIRYASVERLLERLTDLRF-LSIDFLNTFLHSYRVFTNAMVVLDKLINIYR 261
Cdd:pfam00618   1 QVKAGTLEKLVEYLTSTRImLDDSFLSTFLLTYRSFTTPAELLELLIERYN 51

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907195722   9 ENIRKNLAIERMITEGCEILLDTSQTFVRQGSLMQMslseksksSRgrlgslstKKEGERQCFLFSKHLIICTRGSGGKL 88
Cdd:cd01218     4 ANRRRIAAVESCFGGSGQPLVKPGRVLVGEGVLTKV--------CR--------KKPKPRQFFLFNDILVYGSIVINKKK 67

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907195722  89 hLTKNGVISLIDCTLldepENLDDEAKGA-GPEIEHlefkigvePKDSlpFTVIlvASTRQEKAAWTSDIIQC 160
Cdd:cd01218    68 -YNKQRIIPLEDVKI----EDLEDTGELKnGWQIIS--------PKKS--FVVY--AATATEKSEWMDHINKC 123

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 1907195722 597 FENHPALEIAEQLTLLDHLVFKSIPYEEFFGQGWMKAEKY-ERTPYIMKTTKHFNHVSNFIASEIIRNEDISARASAIEK 675
Cdd:cd00155     1 FLSLDPKELAEQLTLLDFELFRKIEPFELLGSLWSKKDKNiHLSPNLERFIERFNNLSNWVASEILLCTNPKKRARLLSK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907195722 676 WVAVADICRCLHNYNAVLEITSSINRSAIFRLKKTWLKVSKQTKSLLDKLQKLVSSDGRFKNLRESLRNC--DPPCVPYL 753
Cdd:cd00155    81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEVLSSKLKKLFEELEELVDPSRNFKNYRKLLKSVgpNPPCVPFL 160

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1907195722 754 GMYLTDLVFIEEGTPNYTEDGLVNFSKMRMISHIIREIRQFQQTTYKIDPQPKVIQYLLD-ESFMLDEESLYESSL 828
Cdd:cd00155   161 GVYLKDLTFLHEGNPDFLEGNLVNFEKRRKIAEILREIRQLQSNSYELNRDEDILAFLWKlLELILNEDELYELSL 236

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
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1907195722 212 QIRYASVERLLERLTDLRF-LSIDFLNTFLHSYRVFTNAMVVLDKLINIYR 261
Cdd:pfam00618   1 QVKAGTLEKLVEYLTSTRImLDDSFLSTFLLTYRSFTTPAELLELLIERYN 51

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 1907195722   9 ENIRKNLAIERMITEGCEILLDTSQTFVRQGSLMQMslseksksSRgrlgslstKKEGERQCFLFSKHLIICTRGSGGKL 88
Cdd:cd01218     4 ANRRRIAAVESCFGGSGQPLVKPGRVLVGEGVLTKV--------CR--------KKPKPRQFFLFNDILVYGSIVINKKK 67

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907195722  89 hLTKNGVISLIDCTLldepENLDDEAKGA-GPEIEHlefkigvePKDSlpFTVIlvASTRQEKAAWTSDIIQC 160
Cdd:cd01218    68 -YNKQRIIPLEDVKI----EDLEDTGELKnGWQIIS--------PKKS--FVVY--AATATEKSEWMDHINKC 123

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907195722 497 SSDQRNIDKEFVIRRAATNRVLNVLRHWVTKHTQDFDTDDTLKYRVICFLEEVMHDPDLL 556
Cdd:cd06224    50 PENLEYNDWDKKKSKPIRLRVLNVLRTWVENYPYDFFDDEELLELLEEFLNRLVQEGALL 109

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907195722  56 RLGSLSTKKEG------ERQCFLFSKHLIICTRGSGGKLHLTKnGVISLIDCTLLDEPENLDDEAKgagpeiehLEFKIg 129
Cdd:pfam00169   3 KEGWLLKKGGGkkkswkKRYFVLFDGSLLYYKDDKSGKSKEPK-GSISLSGCEVVEVVASDSPKRK--------FCFEL- 72

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1907195722 130 VEPKDSLPFTVILVASTRQEKAAWTSDIIQCV 161
Cdd:pfam00169  73 RTGERTGKRTYLLQAESEEERKDWIKAIQSAI 104

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
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1907195722  213 IRYASVERLLERLTD-LRFLSIDFLNTFLHSYRVFTNAMVVLDKLINIYRKP 263
Cdd:smart00229   5 IKGGTLEALIEHLTEaFDKADPSFVETFLLTYRSFITTQELLQLLLYRYNAI 56

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 1907195722 597 FENHPALEIAEQLTLLDHLVFKSIPYEEFFGQGWMKAEKY-ERTPYIMKTTKHFNHVSNFIASEIIRNEDISARASAIEK 675
Cdd:cd00155     1 FLSLDPKELAEQLTLLDFELFRKIEPFELLGSLWSKKDKNiHLSPNLERFIERFNNLSNWVASEILLCTNPKKRARLLSK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907195722 676 WVAVADICRCLHNYNAVLEITSSINRSAIFRLKKTWLKVSKQTKSLLDKLQKLVSSDGRFKNLRESLRNC--DPPCVPYL 753
Cdd:cd00155    81 FIQVAKHCRELNNFNSLMAIVSALSSSPISRLKKTWEVLSSKLKKLFEELEELVDPSRNFKNYRKLLKSVgpNPPCVPFL 160

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1907195722 754 GMYLTDLVFIEEGTPNYTEDGLVNFSKMRMISHIIREIRQFQQTTYKIDPQPKVIQYLLD-ESFMLDEESLYESSL 828
Cdd:cd00155   161 GVYLKDLTFLHEGNPDFLEGNLVNFEKRRKIAEILREIRQLQSNSYELNRDEDILAFLWKlLELILNEDELYELSL 236

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
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1907195722 212 QIRYASVERLLERLTDLRF-LSIDFLNTFLHSYRVFTNAMVVLDKLINIYR 261
Cdd:pfam00618   1 QVKAGTLEKLVEYLTSTRImLDDSFLSTFLLTYRSFTTPAELLELLIERYN 51

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 1907195722   9 ENIRKNLAIERMITEGCEILLDTSQTFVRQGSLMQMslseksksSRgrlgslstKKEGERQCFLFSKHLIICTRGSGGKL 88
Cdd:cd01218     4 ANRRRIAAVESCFGGSGQPLVKPGRVLVGEGVLTKV--------CR--------KKPKPRQFFLFNDILVYGSIVINKKK 67

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907195722  89 hLTKNGVISLIDCTLldepENLDDEAKGA-GPEIEHlefkigvePKDSlpFTVIlvASTRQEKAAWTSDIIQC 160
Cdd:cd01218    68 -YNKQRIIPLEDVKI----EDLEDTGELKnGWQIIS--------PKKS--FVVY--AATATEKSEWMDHINKC 123

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907195722 497 SSDQRNIDKEFVIRRAATNRVLNVLRHWVTKHTQDFDTDDTLKYRVICFLEEVMHDPDLL 556
Cdd:cd06224    50 PENLEYNDWDKKKSKPIRLRVLNVLRTWVENYPYDFFDDEELLELLEEFLNRLVQEGALL 109

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907195722  56 RLGSLSTKKEG------ERQCFLFSKHLIICTRGSGGKLHLTKnGVISLIDCTLLDEPENLDDEAKgagpeiehLEFKIg 129
Cdd:pfam00169   3 KEGWLLKKGGGkkkswkKRYFVLFDGSLLYYKDDKSGKSKEPK-GSISLSGCEVVEVVASDSPKRK--------FCFEL- 72

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1907195722 130 VEPKDSLPFTVILVASTRQEKAAWTSDIIQCV 161
Cdd:pfam00169  73 RTGERTGKRTYLLQAESEEERKDWIKAIQSAI 104

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 1; Members here include FARP1 (also called Chondrocyte-derived ezrin-like protein; PH domain-containing family C member 2), FARP2 (also called FIR/FERM domain including RhoGEF; FGD1-related Cdc42-GEF/FRG), and FARP6 (also called Zinc finger FYVE domain-containing protein 24). They are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. Little is known about FARP1 and FARP6, though FARP1 has increased expression in differentiated chondrocytes. FARP2 is thought to regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac. It is found in brain, lung, and testis, as well as embryonic hippocampal and cortical neurons. FARP1 and FARP2 are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. FARP6 is composed of Dbl-homology (DH), and two C-terminal PH domains separated by a FYVE domain. This hierarchy contains the first PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907195722  55 GRLGSLSTKKEGERQCFLFSKHLIICTRGSGGKLHLTKNGVISLIDCTLldepENLDDEAKGAGPeiehleFKIGVEPKd 134
Cdd:cd01220    12 GCLQKLSKKGLQQRMFFLFSDVLLYTSRSPTPSLQFKVHGQLPLRGLMV----EESEPEWGVAHC------FTIYGGNR- 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1907195722 135 slpfTVILVASTRQEKAAWTSDIIQCVDNIR 165
Cdd:cd01220    81 ----ALTVAASSEEEKERWLEDLQRAIDAAK 107

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 1907195722  55 GRLGSLSTKKEGERQCFLFSKHLIICTRGSGGKLHLTKNGVISLIDCTLldepENLDDeakGAGPEIEHL---EFKIGVE 131
Cdd:cd01224    33 GELTKISAGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDNMEI----EDLPD---GKDDESGVTvknAWKIYNA 105

                          90       100
                  ....*....|....*....|..
gi 1907195722 132 PKDSlpfTVILVASTRQEKAAW 153
Cdd:cd01224   106 SKNK---WYVLCAKSAEEKQRW 124