Ras-specific guanine nucleotide-releasing factors 1 and 2 Pleckstrin homology (PH) domain; RasGRF1 (also called GRF1; CDC25Mm/Ras-specific nucleotide exchange factor CDC25; GNRP/Guanine nucleotide-releasing protein) and RasGRF2 (also called GRF2; Ras guanine nucleotide exchange factor 2) are a family of guanine nucleotide exchange factors (GEFs). They both promote the exchange of Ras-bound GDP by GTP, thereby regulating the RAS signaling pathway. RasGRF1 and RasGRF2 form homooligomers and heterooligomers. GRF1 has 3 isoforms and GRF2 has 2 isoforms. The longest isoforms of RasGRF1 and RasGRF2 contain the following domains: a Rho-GEF domain sandwiched between 2 PH domains, IQ domains, a REM (Ras exchanger motif) domain, and a Ras-GEF domainwhich gives them the capacity to activate both Ras and Rac GTPases in response to signals from a variety of neurotransmitter receptors. Their IQ domains allow them to act as calcium sensors to mediate the actions of NMDA-type and calcium-permeable AMPA-type glutamate receptors. GRF1 also mediates the action of dopamine receptors that signal through cAMP. GRF1 and GRF2 play strikingly different roles in regulating MAP kinase family members, neuronal synaptic plasticity, specific forms of learning and memory, and behavioral responses to psychoactive drugs. 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 1907092992  19 ARKEGTKRGFLSKKAAEASRWHEKWFALYQNVLFYFEGEQSGRPAGMYLLEGCSCERTPAPPRTNAGpagaRDALDKQYY 98
Cdd:cd13261     1 ARKDGTKRGYLSKKTSDSGKWHERWFALYQNLLFYFENESSSRPSGLYLLEGCYCERLPTPKGALKG----KDHLEKQHY 76

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907092992  99 FTVLFGHDGQKPLELRCEEEQAGKEWMEAIHQASYADILIEREVLMQKYIHLVQIVETEK 158
Cdd:cd13261    77 FTISFRHENQRQYELRAETESDCDEWVEAIKQASFNKLLLQKEELEQKYLHLLQIVESEK 136

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 1907092992 638 QIRYASVERLLERLTDLRF-LSIDFLNTFLHTYRIFTTATVVLAKLSDIY 686
Cdd:pfam00618   1 QVKAGTLEKLVEYLTSTRImLDDSFLSTFLLTYRSFTTPAELLELLIERY 50

Ras-specific guanine nucleotide-releasing factors 1 and 2 Pleckstrin homology (PH) domain; RasGRF1 (also called GRF1; CDC25Mm/Ras-specific nucleotide exchange factor CDC25; GNRP/Guanine nucleotide-releasing protein) and RasGRF2 (also called GRF2; Ras guanine nucleotide exchange factor 2) are a family of guanine nucleotide exchange factors (GEFs). They both promote the exchange of Ras-bound GDP by GTP, thereby regulating the RAS signaling pathway. RasGRF1 and RasGRF2 form homooligomers and heterooligomers. GRF1 has 3 isoforms and GRF2 has 2 isoforms. The longest isoforms of RasGRF1 and RasGRF2 contain the following domains: a Rho-GEF domain sandwiched between 2 PH domains, IQ domains, a REM (Ras exchanger motif) domain, and a Ras-GEF domainwhich gives them the capacity to activate both Ras and Rac GTPases in response to signals from a variety of neurotransmitter receptors. Their IQ domains allow them to act as calcium sensors to mediate the actions of NMDA-type and calcium-permeable AMPA-type glutamate receptors. GRF1 also mediates the action of dopamine receptors that signal through cAMP. GRF1 and GRF2 play strikingly different roles in regulating MAP kinase family members, neuronal synaptic plasticity, specific forms of learning and memory, and behavioral responses to psychoactive drugs. 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 1907092992  19 ARKEGTKRGFLSKKAAEASRWHEKWFALYQNVLFYFEGEQSGRPAGMYLLEGCSCERTPAPPRTNAGpagaRDALDKQYY 98
Cdd:cd13261     1 ARKDGTKRGYLSKKTSDSGKWHERWFALYQNLLFYFENESSSRPSGLYLLEGCYCERLPTPKGALKG----KDHLEKQHY 76

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907092992  99 FTVLFGHDGQKPLELRCEEEQAGKEWMEAIHQASYADILIEREVLMQKYIHLVQIVETEK 158
Cdd:cd13261    77 FTISFRHENQRQYELRAETESDCDEWVEAIKQASFNKLLLQKEELEQKYLHLLQIVESEK 136

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 1907092992 244 RNQIVFTMVEAETEYVHQLYILVNGFLRPLRMAASskkpPINHDDVSSIFLNSETIMFLHEIFHQGLKARLANWPTLV-- 321
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELL----PLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKSGpr 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907092992 322 LADLFDILLPMLNIYQEFVRNHQYSLQVLANCKQ-NRDFDKLLKQYEANpaCEGRMLETFLTYPMFQIPRYIITLHELLA 400
Cdd:cd00160    77 IGDVFLKLAPFFKIYSEYCSNHPDALELLKKLKKfNKFFQEFLEKAESE--CGRLKLESLLLKPVQRLTKYPLLLKELLK 154

                         170       180
                  ....*....|....*....|....
gi 1907092992 401 HTPHEHVERKSLEFAKSKLEELSR 424
Cdd:cd00160   155 HTPDGHEDREDLKKALEAIKEVAS 178

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 1907092992 638 QIRYASVERLLERLTDLRF-LSIDFLNTFLHTYRIFTTATVVLAKLSDIY 686
Cdd:pfam00618   1 QVKAGTLEKLVEYLTSTRImLDDSFLSTFLLTYRSFTTPAELLELLIERY 50

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 1907092992   24 TKRGFLSKKAAEASR-WHEKWFALYQNVLFYFE---GEQSGRPAGMYLLEGCSCERTPAPprtnagpagarDALDKQYYF 99
Cdd:smart00233   2 IKEGWLYKKSGGGKKsWKKRYFVLFNSTLLYYKskkDKKSYKPKGSIDLSGCTVREAPDP-----------DSSKKPHCF 70

                           90       100       110
                   ....*....|....*....|....*....|....
gi 1907092992  100 TVLfgHDGQKPLELRCEEEQAGKEWMEAIHQASY 133
Cdd:smart00233  71 EIK--TSDRKTLLLQAESEEEREKWVEALRKAIA 102

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 1907092992  480 VRLGSLSLKKEG------ERQCFLFTKHFLICTRSSGGKLHLLKtgGVLSLIQCTLIEEPDGSDDDPKGSghmfghldFK 553
Cdd:smart00233   2 IKEGWLYKKSGGgkkswkKRYFVLFNSTLLYYKSKKDKKSYKPK--GSIDLSGCTVREAPDPDSSKKPHC--------FE 71

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1907092992  554 IVVEPPDaasfTVVLLAPSRQEKAAWMSDISQCVD 588
Cdd:smart00233  72 IKTSDRK----TLLLQAESEEEREKWVEALRKAIA 102

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 1907092992  635 KVPQIRYASVERLLERLTD-LRFLSIDFLNTFLHTYRIFTTATVVLAKLSDIYKRPF 690
Cdd:smart00229   1 DGGLIKGGTLEALIEHLTEaFDKADPSFVETFLLTYRSFITTQELLQLLLYRYNAIP 57

Ras-specific guanine nucleotide-releasing factors 1 and 2 Pleckstrin homology (PH) domain; RasGRF1 (also called GRF1; CDC25Mm/Ras-specific nucleotide exchange factor CDC25; GNRP/Guanine nucleotide-releasing protein) and RasGRF2 (also called GRF2; Ras guanine nucleotide exchange factor 2) are a family of guanine nucleotide exchange factors (GEFs). They both promote the exchange of Ras-bound GDP by GTP, thereby regulating the RAS signaling pathway. RasGRF1 and RasGRF2 form homooligomers and heterooligomers. GRF1 has 3 isoforms and GRF2 has 2 isoforms. The longest isoforms of RasGRF1 and RasGRF2 contain the following domains: a Rho-GEF domain sandwiched between 2 PH domains, IQ domains, a REM (Ras exchanger motif) domain, and a Ras-GEF domainwhich gives them the capacity to activate both Ras and Rac GTPases in response to signals from a variety of neurotransmitter receptors. Their IQ domains allow them to act as calcium sensors to mediate the actions of NMDA-type and calcium-permeable AMPA-type glutamate receptors. GRF1 also mediates the action of dopamine receptors that signal through cAMP. GRF1 and GRF2 play strikingly different roles in regulating MAP kinase family members, neuronal synaptic plasticity, specific forms of learning and memory, and behavioral responses to psychoactive drugs. 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 1907092992  19 ARKEGTKRGFLSKKAAEASRWHEKWFALYQNVLFYFEGEQSGRPAGMYLLEGCSCERTPAPPRTNAGpagaRDALDKQYY 98
Cdd:cd13261     1 ARKDGTKRGYLSKKTSDSGKWHERWFALYQNLLFYFENESSSRPSGLYLLEGCYCERLPTPKGALKG----KDHLEKQHY 76

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907092992  99 FTVLFGHDGQKPLELRCEEEQAGKEWMEAIHQASYADILIEREVLMQKYIHLVQIVETEK 158
Cdd:cd13261    77 FTISFRHENQRQYELRAETESDCDEWVEAIKQASFNKLLLQKEELEQKYLHLLQIVESEK 136

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 1907092992 244 RNQIVFTMVEAETEYVHQLYILVNGFLRPLRMAASskkpPINHDDVSSIFLNSETIMFLHEIFHQGLKARLANWPTLV-- 321
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELL----PLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKSGpr 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907092992 322 LADLFDILLPMLNIYQEFVRNHQYSLQVLANCKQ-NRDFDKLLKQYEANpaCEGRMLETFLTYPMFQIPRYIITLHELLA 400
Cdd:cd00160    77 IGDVFLKLAPFFKIYSEYCSNHPDALELLKKLKKfNKFFQEFLEKAESE--CGRLKLESLLLKPVQRLTKYPLLLKELLK 154

                         170       180
                  ....*....|....*....|....
gi 1907092992 401 HTPHEHVERKSLEFAKSKLEELSR 424
Cdd:cd00160   155 HTPDGHEDREDLKKALEAIKEVAS 178

Sesquipedalian family Pleckstrin homology (PH) domain; The sesquipedalian family has 2 mammalian members: Ses1 and Ses2, which are also callled 7 kDa inositol polyphosphate phosphatase-interacting protein 1 and 2. They play a role in endocytic trafficking and are required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane. Members of this family form homodimers and heterodimers. Sesquipedalian interacts with inositol polyphosphate 5-phosphatase OCRL-1 (INPP5F) also known as Lowe oculocerebrorenal syndrome protein, a phosphatase enzyme that is involved in actin polymerization and is found in the trans-Golgi network and INPP5B. Sesquipedalian contains a single 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 1907092992  25 KRGFLSKKAAEASRWHEKWFALYQNVLFYFEGEQSGRPAGMYLLEGCSCERTPApprtnagpagardalDKQYYFTVLFG 104
Cdd:cd13288    10 KEGYLWKKGERNTSYQKRWFVLKGNLLFYFEKKGDREPLGVIVLEGCTVELAED---------------AEPYAFAIRFD 74

                          90       100
                  ....*....|....*....|....*....
gi 1907092992 105 HDGQKPLELRCEEEQAGKEWMEAIHQASY 133
Cdd:cd13288    75 GPGARSYVLAAENQEDMESWMKALSRASY 103

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907092992  24 TKRGFLSKKA-AEASRWHEKWFALYQNVLFYFE---GEQSGRPAGMYLLEGCSCERTPAPPRTNagpagardaldKQYYF 99
Cdd:pfam00169   2 VKEGWLLKKGgGKKKSWKKRYFVLFDGSLLYYKddkSGKSKEPKGSISLSGCEVVEVVASDSPK-----------RKFCF 70

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1907092992 100 TVLFGH-DGQKPLELRCEEEQAGKEWMEAIHQASY 133
Cdd:pfam00169  71 ELRTGErTGKRTYLLQAESEEERKDWIKAIQSAIR 105

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907092992   6 RYNEGHalyLAMLARKEGTKRGFLSKKAAEASR----WHEKWFALYQNVLFYF---EGEQSGRPAGMYLLEGCSCERTPA 78
Cdd:cd13258     2 RFNEKE---LAALSSQPAEKEGKIAERQMGGPKksevFKERWFKLKGNLLFYFrtnEFGDCSEPIGAIVLENCRVQMEEI 78

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1907092992  79 PPRTNAgpagardaldkqyyFTVLFGHDGQKPLELRCEEEQAGKEWMEAIHQASY 133
Cdd:cd13258    79 TEKPFA--------------FSIVFNDEPEKKYIFSCRSEEQCEQWIEALRQASY 119

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
                  ....*....|....*....|....*....|....*....|....*...
gi 1907092992 643 SVERLLERLTD-LRFLSIDFLNTFLHTYRIFTTATVVLAKLSDIYKRP 689
Cdd:cd06224     1 TLEALIEHLTStFDMPDPSFVSTFLLTYRSFTTPTELLEKLIERYEIA 48

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 1907092992  25 KRGFLSKKAAEAS-RWHEKWFALYQNVLFYF--EGEQSGRPAGMYLLEGCsCERTPAPPrtnagpagardaLDKQYYFTV 101
Cdd:cd00821     1 KEGYLLKRGGGGLkSWKKRWFVLFEGVLLYYksKKDSSYKPKGSIPLSGI-LEVEEVSP------------KERPHCFEL 67

                          90       100
                  ....*....|....*....|....*..
gi 1907092992 102 LfgHDGQKPLELRCEEEQAGKEWMEAI 128
Cdd:cd00821    68 V--TPDGRTYYLQADSEEERQEWLKAL 92

Rho GTPase activating protein 25 and related proteins Pleckstrin homology (PH) domain; RhoGAP25 (also called ArhGap25) like other RhoGaps are involved in cell polarity, cell morphology and cytoskeletal organization. They act as GTPase activators for the Rac-type GTPases by converting them to an inactive GDP-bound state and control actin remodeling by inactivating Rac downstream of Rho leading to suppress leading edge protrusion and promotes cell retraction to achieve cellular polarity and are able to suppress RAC1 and CDC42 activity in vitro. Overexpression of these proteins induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia. This hierarchy contains RhoGAP22, RhoGAP24, and RhoGAP25. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) 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 1907092992  22 EGTKRGFLSKKAAEASRWHEKWFALYQNVLFYFEGEQSGRPAGMYLLEGCSCERTPAPPrtnagpagarDALDKqYYFTV 101
Cdd:cd13263     2 RPIKSGWLKKQGSIVKNWQQRWFVLRGDQLYYYKDEDDTKPQGTIPLPGNKVKEVPFNP----------EEPGK-FLFEI 70

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1907092992 102 LFGHDGQKPLE-----LRCEEEQAG-KEWMEAIHQASYA 134
Cdd:cd13263    71 IPGGGGDRMTSnhdsyLLMANSQAEmEEWVKVIRRVIGS 109

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 1907092992  480 VRLGSLSLKKEG------ERQCFLFTKHFLICTRSSGGKLHLLKtgGVLSLIQCTLIEEPDGSDDDPKGSghmfghldFK 553
Cdd:smart00233   2 IKEGWLYKKSGGgkkswkKRYFVLFNSTLLYYKSKKDKKSYKPK--GSIDLSGCTVREAPDPDSSKKPHC--------FE 71

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1907092992  554 IVVEPPDaasfTVVLLAPSRQEKAAWMSDISQCVD 588
Cdd:smart00233  72 IKTSDRK----TLLLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907092992 480 VRLGSLSLKKEG------ERQCFLFTKHFLICTRSSGGKLHLLKtgGVLSLIQCTLIEEPDGSDDDPKgsgHMFghldfk 553
Cdd:pfam00169   2 VKEGWLLKKGGGkkkswkKRYFVLFDGSLLYYKDDKSGKSKEPK--GSISLSGCEVVEVVASDSPKRK---FCF------ 70

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1907092992 554 IVVEPPDAASFTVVLLAPSRQEKAAWMSDISQCV 587
Cdd:pfam00169  71 ELRTGERTGKRTYLLQAESEEERKDWIKAIQSAI 104

Switch-associated protein-70 Pleckstrin homology (PH) domain; SWAP-70 (also called Differentially expressed in FDCP 6/DEF-6 or IRF4-binding protein) functions in cellular signal transduction pathways (in conjunction with Rac), regulates cell motility through actin rearrangement, and contributes to the transformation and invasion activity of mouse embryo fibroblasts. Metazoan SWAP-70 is found in B lymphocytes, mast cells, and in a variety of organs. Metazoan SWAP-70 contains an N-terminal EF-hand motif, a centrally located PH domain, and a C-terminal coiled-coil domain. The PH domain of Metazoan SWAP-70 contains a phosphoinositide-binding site and a nuclear localization signal (NLS), which localize SWAP-70 to the plasma membrane and nucleus, respectively. The NLS is a sequence of four Lys residues located at the N-terminus of the C-terminal a-helix; this is a unique characteristic of the Metazoan SWAP-70 PH domain. The SWAP-70 PH domain binds PtdIns(3,4,5)P3 and PtdIns(4,5)P2 embedded in lipid bilayer vesicles. There are additional plant SWAP70 proteins, but these are not included in this hierarchy. Rice SWAP70 (OsSWAP70) exhibits GEF activity toward the its Rho GTPase, OsRac1, and regulates chitin-induced production of reactive oxygen species and defense gene expression in rice. Arabidopsis SWAP70 (AtSWAP70) plays a role in both PAMP- and effector-triggered immunity. Plant SWAP70 contains both DH and PH domains, but their arrangement is the reverse of that in typical DH-PH-type Rho GEFs, wherein the DH domain is flanked by a C-terminal 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 1907092992  25 KRGFLSKKAAEASRWHEKWFALYQNVLFYFEGEQSGRPAGMYLL-EGCSCErtPAPPRTnagpagardalDKQYYFTVlf 103
Cdd:cd13273    10 KKGYLWKKGHLLPTWTERWFVLKPNSLSYYKSEDLKEKKGEIALdSNCCVE--SLPDRE-----------GKKCRFLV-- 74

                          90       100
                  ....*....|....*....|....*...
gi 1907092992 104 gHDGQKPLELRCEEEQAGKEWMEAIHQA 131
Cdd:cd13273    75 -KTPDKTYELSASDHKTRQEWIAAIQTA 101

Dual Adaptor for Phosphotyrosine and 3-Phosphoinositides Pleckstrin homology (PH) domain; DAPP1 (also known as PHISH/3' phosphoinositide-interacting SH2 domain-containing protein or Bam32) plays a role in B-cell activation and has potential roles in T-cell and mast cell function. DAPP1 promotes B cell receptor (BCR) induced activation of Rho GTPases Rac1 and Cdc42, which feed into mitogen-activated protein kinases (MAPK) activation pathways and affect cytoskeletal rearrangement. DAPP1can also regulate BCR-induced activation of extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK). DAPP1 contains an N-terminal SH2 domain and a C-terminal pleckstrin homology (PH) domain with a single tyrosine phosphorylation site located centrally. DAPP1 binds strongly to both PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The PH domain is essential for plasma membrane recruitment of PI3K upon cell activation. 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907092992  23 GTKRGFLSKKAAEASRWHEKWFALYQNVLFYFEGEQSGRP-AGMYLLEGCSCERTPAPPRTNA 84
Cdd:cd10573     3 GSKEGYLTKLGGIVKNWKTRWFVLRRNELKYFKTRGDTKPiRVLDLRECSSVQRDYSQGKVNC 65

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 1907092992 460 FIRQGSLIqvpsvergKLSKvrlgslslKKEGERQCFLFTKHFLICTRSSGGKLHLlKTGGVLSLiQCTLIEEPDgsddD 539
Cdd:cd01220     8 FIREGCLQ--------KLSK--------KGLQQRMFFLFSDVLLYTSRSPTPSLQF-KVHGQLPL-RGLMVEESE----P 65

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1907092992 540 PKGSGHMFghldfKIvveppDAASFTVVLLAPSRQEKAAWMSDISQCVDNIR 591
Cdd:cd01220    66 EWGVAHCF-----TI-----YGGNRALTVAASSEEEKERWLEDLQRAIDAAK 107

General Receptor for Phosphoinositides-1-like Pleckstrin homology (PH) domain; GRP1/cytohesin3 and the related proteins ARNO (ARF nucleotide-binding site opener)/cytohesin-2 and cytohesin-1 are ARF exchange factors that contain a pleckstrin homology (PH) domain thought to target these proteins to cell membranes through binding polyphosphoinositides. The PH domains of all three proteins exhibit relatively high affinity for PtdIns(3,4,5)P3. Within the Grp1 family, diglycine (2G) and triglycine (3G) splice variants, differing only in the number of glycine residues in the PH domain, strongly influence the affinity and specificity for phosphoinositides. The 2G variants selectively bind PtdIns(3,4,5)P3 with high affinity,the 3G variants bind PtdIns(3,4,5)P3 with about 30-fold lower affinity and require the polybasic region for plasma membrane targeting. These ARF-GEFs share a common, tripartite structure consisting of an N-terminal coiled-coil domain, a central domain with homology to the yeast protein Sec7, a PH domain, and a C-terminal polybasic region. The Sec7 domain is autoinhibited by conserved elements proximal to the PH domain. GRP1 binds to the DNA binding domain of certain nuclear receptors (TRalpha, TRbeta, AR, ER, but not RXR), and can repress thyroid hormone receptor (TR)-mediated transactivation by decreasing TR-complex formation on thyroid hormone response elements. ARNO promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion. Cytohesin acts as a PI 3-kinase effector mediating biological responses including cell spreading and adhesion, chemotaxis, protein trafficking, and cytoskeletal rearrangements, only some of which appear to depend on their ability to activate ARFs. 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
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1907092992  25 KRGFLSKKAAEASRWHEKWFALYQNVLFYFEGEQSGRPAGMYLLEGCSCERTPAPPRTN 83
Cdd:cd01252     5 REGWLLKLGGRVKSWKRRWFILTDNCLYYFEYTTDKEPRGIIPLENLSVREVEDKKKPF 63

SifA and kinesin-interacting protein Pleckstrin homology (PH) domain; SKIP (also called PLEKHM2/Pleckstrin homology domain-containing family M member 2) is a soluble cytosolic protein that contains a RUN domain and a PH domain separated by a unstructured linker region. SKIP is a target of the Salmonella effector protein SifA and the SifA-SKIP complex regulates kinesin-1 on the bacterial vacuole. The PH domain of SKIP binds to the N-terminal region of SifA while the N-terminus of SKIP is proposed to bind the TPR domain of the kinesin light chain. The opposite side of the SKIP PH domain is proposed to bind phosphoinositides. TSifA, SKIP, SseJ, and RhoA family GTPases are also thought to promote host membrane tubulation. Recently, it was shown that the lysosomal GTPase Arl8 binds to the kinesin-1 linker SKIP and that both are required for the normal intracellular distribution of lysosomes. Interestingly, two kinesin light chain binding motifs (WD) in SKIP have now been identified to match a consensus sequence for a kinesin light chain binding site found in several proteins including calsyntenin-1/alcadein, caytaxin, and vaccinia virus A36. SKIP has also been shown to interact with Rab1A. 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 1907092992  24 TKRGFLSKKAAEASRWHEKW----FALYQNVLFYFEGEQSGRPAGMYLLEGCSCErtpapprtnagpaGARDAL--DKQY 97
Cdd:cd13309     1 TKEGMLMYKTGTSYLGGETWkpgyFLLKNGVLYQYPDRSDRLPLLSISLGGEQCG-------------GCRRINntERPH 67

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1907092992  98 YFTVLFGhdGQKPLELRCEEEQAGKEWMEAIHQAS 132
Cdd:cd13309    68 TFELILT--DRSSLELAAPDEYEASEWLQSLCQSA 100

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 1907092992 475 GKLSKvrLGSLSLKKEGERQCFLFtKHFLICTRSSGGKLHLLKtgGVLSLIQCTLIEEPDGSDDDPKgsghmfghldFKI 554
Cdd:cd00821     3 GYLLK--RGGGGLKSWKKRWFVLF-EGVLLYYKSKKDSSYKPK--GSIPLSGILEVEEVSPKERPHC----------FEL 67

                          90       100
                  ....*....|....*....|....*....
gi 1907092992 555 VVEPPDaasfTVVLLAPSRQEKAAWMSDI 583
Cdd:cd00821    68 VTPDGR----TYYLQADSEEERQEWLKAL 92