FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 2; 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 second 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 805753508 478 QNQLSGFLLRKFKNSNGWQKLWVVFTNFCLFFYKSHRDDFPLASLPLLGYTVTTPSEKDGINKDFVFKLQFKSHVYFFRA 557
Cdd:cd13235    2 ENQMSGYLLRKFKNSNGWQKLWVVFTNFCLFFYKSHQDEFPLASLPLLGYSVGLPSEADNIDKDYVFKLQFKSHVYFFRA 81

                         90
                 ....*....|....*..
gi 805753508 558 ESDYTFGRWIEVIRSAT 574
Cdd:cd13235   82 ESEYTFERWMEVIRSAT 98

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 805753508 104 YYIAKELLMTERTYKKDLDVINVWFREE-VSRETELEGEAVVSL---IELLADVHGPCLQEMEARLERWESNArHNIGD- 178
Cdd:cd00160    2 QEVIKELLQTERNYVRDLKLLVEVFLKPlDKELLPLSPEEVELLfgnIEEIYEFHRIFLKSLEERVEEWDKSG-PRIGDv 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 805753508 179 FLynTLLNVLPLYDQYLENLIPVLEKMEYYTRTSRRFDQLCRDFEAQKHcYLPLTSFLLKPLQRLLHYNSIIDRLLDHYP 258
Cdd:cd00160   81 FL--KLAPFFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLEKAESECG-RLKLESLLLKPVQRLTKYPLLLKELLKHTP 157

                        170
                 ....*....|....
gi 805753508 259 KDHTDFEDCLAARD 272
Cdd:cd00160  158 DGHEDREDLKKALE 171

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 2; 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 second 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 805753508 478 QNQLSGFLLRKFKNSNGWQKLWVVFTNFCLFFYKSHRDDFPLASLPLLGYTVTTPSEKDGINKDFVFKLQFKSHVYFFRA 557
Cdd:cd13235    2 ENQMSGYLLRKFKNSNGWQKLWVVFTNFCLFFYKSHQDEFPLASLPLLGYSVGLPSEADNIDKDYVFKLQFKSHVYFFRA 81

                         90
                 ....*....|....*..
gi 805753508 558 ESDYTFGRWIEVIRSAT 574
Cdd:cd13235   82 ESEYTFERWMEVIRSAT 98

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 805753508 104 YYIAKELLMTERTYKKDLDVINVWFREE-VSRETELEGEAVVSL---IELLADVHGPCLQEMEARLERWESNArHNIGD- 178
Cdd:cd00160    2 QEVIKELLQTERNYVRDLKLLVEVFLKPlDKELLPLSPEEVELLfgnIEEIYEFHRIFLKSLEERVEEWDKSG-PRIGDv 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 805753508 179 FLynTLLNVLPLYDQYLENLIPVLEKMEYYTRTSRRFDQLCRDFEAQKHcYLPLTSFLLKPLQRLLHYNSIIDRLLDHYP 258
Cdd:cd00160   81 FL--KLAPFFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLEKAESECG-RLKLESLLLKPVQRLTKYPLLLKELLKHTP 157

                        170
                 ....*....|....
gi 805753508 259 KDHTDFEDCLAARD 272
Cdd:cd00160  158 DGHEDREDLKKALE 171

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 805753508  106 IAKELLMTERTYKKDLDVINVWFREEVS---RETELEGEAVVSLIELLADVHGpclQE-MEARLERWESNarHNIGDFLY 181
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSkplSESEEEIKTIFSNIEEIYELHR---QLlLEELLKEWISI--QRIGDIFL 75

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 805753508  182 NtLLNVLPLYDQYLENLIPVLEKMEYYTRTSRRFDQLCRDFEAQKHCY-LPLTSFLLKPLQRLLHYNSIIDRLLDHYPKD 260
Cdd:pfam00621  76 K-FAPGFKVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRgLDLNSFLIKPVQRIPRYPLLLKELLKHTPPD 154

                         170
                  ....*....|
gi 805753508  261 HTDFEDCLAA 270
Cdd:pfam00621 155 HPDYEDLKKA 164

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 805753508   314 FIRQGCLQKYS---RKGFQQRMFFLFSDILLYtFRTQQSTQCFRVHGQLPLKGMKIRESDNKT--GSDYAFMIDAQGNQS 388
Cdd:smart00233   1 VIKEGWLYKKSgggKKSWKKRYFVLFNSTLLY-YKSKKDKKSYKPKGSIDLSGCTVREAPDPDssKKPHCFEIKTSDRKT 79

                           90       100
                   ....*....|....*....|...
gi 805753508   389 LTVAASNEEEKERWLEDLTQAIA 411
Cdd:smart00233  80 LLLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 805753508  315 IRQGCLQKYS---RKGFQQRMFFLFSDILLYtFRTQQSTQCFRVHGQLPLKGMKIRE--SDNKTGSDYAFMI---DAQGN 386
Cdd:pfam00169   2 VKEGWLLKKGggkKKSWKKRYFVLFDGSLLY-YKDDKSGKSKEPKGSISLSGCEVVEvvASDSPKRKFCFELrtgERTGK 80

                          90       100
                  ....*....|....*....|....*
gi 805753508  387 QSLTVAASNEEEKERWLEDLTQAIA 411
Cdd:pfam00169  81 RTYLLQAESEEERKDWIKAIQSAIR 105

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 2; 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 second 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 805753508 478 QNQLSGFLLRKFKNSNGWQKLWVVFTNFCLFFYKSHRDDFPLASLPLLGYTVTTPSEKDGINKDFVFKLQFKSHVYFFRA 557
Cdd:cd13235    2 ENQMSGYLLRKFKNSNGWQKLWVVFTNFCLFFYKSHQDEFPLASLPLLGYSVGLPSEADNIDKDYVFKLQFKSHVYFFRA 81

                         90
                 ....*....|....*..
gi 805753508 558 ESDYTFGRWIEVIRSAT 574
Cdd:cd13235   82 ESEYTFERWMEVIRSAT 98

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6, N-terminal Pleckstrin Homology (PH) domain; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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 805753508 303 GFDNLVQEGRRFIRQGCLQKYSRKGFQQRMFFLFSDILLYTfRTQQSTQCFRVHGQLPLKGMKI-RESDNKTgsDYAFMI 381
Cdd:cd13389    3 GQYNIVKPGRKLIKEGELMKVSRKEMQPRYFFLFNDCLLYT-TPVQSSGMLKLNNELPLSGMKVkLPEDEEY--SNEFQI 79

                         90       100
                 ....*....|....*....|....*....
gi 805753508 382 DAQgNQSLTVAASNEEEKERWLEDLTQAI 410
Cdd:cd13389   80 IST-KRSFTLIASSEEERDEWVKALSRAI 107

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 805753508   106 IAKELLMTERTYKKDLDVINVWFREEVSRETEL----EGEAVVSLIELLADVHGPCLQEMEARLERWEsnarhNIGDFLY 181
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKLlspnELETLFGNIEEIYEFHRDFLDELEERIEEWD-----DSVERIG 75

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 805753508   182 NTLLNVLPLYDQYLE------NLIPVLEKMeyytRTSRRFDQLCRDFEAQKHCY-LPLTSFLLKPLQRLLHYNSIIDRLL 254
Cdd:smart00325  76 DVFLKLEEFFKIYSEycsnhpDALELLKKL----KKNPRFQKFLKEIESSPQCRrLTLESLLLKPVQRLTKYPLLLKELL 151

                          170       180
                   ....*....|....*....|
gi 805753508   255 DHYPKDHTDFEDCLAARDRL 274
Cdd:smart00325 152 KHTPEDHEDREDLKKALKAI 171

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 805753508 286 NQAENLVQLCEMQRDIGGF-DNLVQEGRRFIRQGCLQKYSRKGFQQRMFFLFSDILLYTFRTQQSTQcFRVHGQLPLKGM 364
Cdd:cd01218    1 NSEANRRRIAAVESCFGGSgQPLVKPGRVLVGEGVLTKVCRKKPKPRQFFLFNDILVYGSIVINKKK-YNKQRIIPLEDV 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 805753508 365 KIRESDNKTGSDYAFMIDAqGNQSLTVAASNEEEKERWLEDLTQA 409
Cdd:cd01218   80 KIEDLEDTGELKNGWQIIS-PKKSFVVYAATATEKSEWMDHINKC 123

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6 pleckstrin homology (PH) domain, C-terminus; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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 805753508 481 LSGFLLRKFKNSNGWQKLWVVFTNFCLFFYKSHRDDFPLASLPLLGYTVTTPSEKDGINKDFVFKLQFKSHVYF-FRAES 559
Cdd:cd13237    1 MSGYLQRRKKSKKSWKRLWFVLKDKVLYTYKASEDVVALESVPLLGFTVVTIDESFEEDESLVFQLLHKGQLPIiFRADD 80

                         90
                 ....*....|.
gi 805753508 560 DYTFGRWIEVI 570
Cdd:cd13237   81 AETAQRWIEAL 91

Phosphoinositol 3-phosphate binding proteins 1, 2, and 3 pleckstrin homology (PH) domain; PEPP1 (also called PLEKHA4/PH domain-containing family A member 4 and RHOXF1/Rhox homeobox family member 1), and related homologs PEPP2 (also called PLEKHA5/PH domain-containing family A member 5) and PEPP3 (also called PLEKHA6/PH domain-containing family A member 6), have PH domains that interact specifically with PtdIns(3,4)P3. Other proteins that bind PtdIns(3,4)P3 specifically are: TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns3P AtPH1, and Ptd- Ins(3,5)P2 (centaurin-beta2). All of these proteins contain at least 5 of the 6 conserved amino acids that make up the putative phosphatidylinositol 3,4,5- trisphosphate-binding motif (PPBM) located at their N-terminus. 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 805753508 495 WQKLWVVFTNFCLFFYKSHRDDFPLASLPLLGYTVTTPSEKDGINKDFVFKL-QFKSHVYFFRAESDYTFGRWIEVIRSA 573
Cdd:cd13248   24 WRKRWFVLKDNCLYYYKDPEEEKALGSILLPSYTISPAPPSDEISRKFAFKAeHANMRTYYFAADTAEEMEQWMNAMSLA 103

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 805753508  482 SGFLLRKFK-NSNGWQKLWVVFTNFCLFFYK---SHRDDFPLASLPLLGYTVTTPSEKDGINKDFVFKL----QFKSHVY 553
Cdd:pfam00169   4 EGWLLKKGGgKKKSWKKRYFVLFDGSLLYYKddkSGKSKEPKGSISLSGCEVVEVVASDSPKRKFCFELrtgeRTGKRTY 83

                          90       100
                  ....*....|....*....|
gi 805753508  554 FFRAESDYTFGRWIEVIRSA 573
Cdd:pfam00169  84 LLQAESEEERKDWIKAIQSA 103

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins pleckstrin homology (PH) domain, C-terminus; 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). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. However, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells and while FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. They also reciprocally regulated cell motility in inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration while FGD3 inhibited it. FGD1 and FGD3 therefore play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP). FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 805753508 481 LSGFLlRKFKNSNGWQKLWVVFTN---FCLFFYKSHRDDFPLASLPLLGYTVTTPSEKDGINKDFVFKLQFKSHVYFFRA 557
Cdd:cd13236   10 LCGFL-QYSEKGKTWQKVWCVIPRtepLVLYLYGAPQDVRAQRTIPLPGCEVTVPPPEERLDGRHVFKLSQSKQSHYFSA 88

                         90
                 ....*....|....*.
gi 805753508 558 ESDYTFGRWIEVIRSA 573
Cdd:cd13236   89 ESEELQQRWLEALSRA 104

Pleckstrin 2 Pleckstrin homology (PH) domain, repeat 1; Pleckstrin is a protein found in platelets. This name is derived from platelet and leukocyte C kinase substrate and the KSTR string of amino acids. Pleckstrin 2 contains two PH domains and a DEP (dishvelled, egl-10, and pleckstrin) domain. Unlike pleckstrin 1, pleckstrin 2 does not contain obvious sites of PKC phosphorylation. Pleckstrin 2 plays a role in actin rearrangement, large lamellipodia and peripheral ruffle formation, and may help orchestrate cytoskeletal arrangement. The PH domains of pleckstrin 2 are thought to contribute to lamellipodia formation. This cd contains the first PH domain 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 805753508 483 GFLLRKFKNSNGWQKLWVVFTNFCLFFYKSHRDDFPLASLPLLGYTVTTPSEKDGiNKDFVFKLQF-KSHVYFFRAESDY 561
Cdd:cd13301    7 GYLVKKGHVVNNWKARWFVLKEDGLEYYKKKTDSSPKGMIPLKGCTITSPCLEYG-KRPLVFKLTTaKGQEHFFQACSRE 85

                         90
                 ....*....|....*....
gi 805753508 562 TFGRWIEVIRSATQQSHVS 580
Cdd:cd13301   86 ERDAWAKDITKAITCLEGG 104

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 805753508 316 RQGCLQKYS---RKGFQQRMFFLFSDILLYTfrTQQSTQCFRVHGQLPLKGMKIRESDNKTGSDYAFMIDAQGNQSLTVA 392
Cdd:cd00821    1 KEGYLLKRGgggLKSWKKRWFVLFEGVLLYY--KSKKDSSYKPKGSIPLSGILEVEEVSPKERPHCFELVTPDGRTYYLQ 78

                         90
                 ....*....|....
gi 805753508 393 ASNEEEKERWLEDL 406
Cdd:cd00821   79 ADSEEERQEWLKAL 92

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 805753508  315 IRQGCLQKYS---RKGFQQRMFFLFSDILLYtFRTQQSTQCFRVHGQLPLKGMKIRE--SDNKTGSDYAFMI---DAQGN 386
Cdd:pfam00169   2 VKEGWLLKKGggkKKSWKKRYFVLFDGSLLY-YKDDKSGKSKEPKGSISLSGCEVVEvvASDSPKRKFCFELrtgERTGK 80

                          90       100
                  ....*....|....*....|....*
gi 805753508  387 QSLTVAASNEEEKERWLEDLTQAIA 411
Cdd:pfam00169  81 RTYLLQAESEEERKDWIKAIQSAIR 105

Cloned out of library/PAK-interactive exchange factor pleckstrin homology (PH) domain; There are two forms of Pix proteins: alpha Pix (also called Rho guanine nucleotide exchange factor (GEF) 6/90Cool-2) and beta Pix (GEF7/p85Cool-1). betaPix contains an N-terminal SH3 domain, a RhoGEF/DH domain, a PH domain, a GIT1 binding domain (GBD), and a C-terminal coiled-coil (CC) domain. alphaPix differs in that it contains a calponin homology (CH) domain, which interacts with beta-parvin, N-terminal to the SH3 domain. alphaPix is an exchange factor for Rac1 and Cdc42 and mediates Pak activation on cell adhesion to fibronectin. Mutations in alphaPix can cause X-linked mental retardation. alphaPix also interacts with Huntington's disease protein (htt), and enhances the aggregation of mutant htt (muthtt) by facilitating SDS-soluble muthtt-muthtt interactions. The DH-PH domain of a Pix was required for its binding to htt. In the majority of Rho GEF proteins, the DH-PH domain is responsible for the exchange activity. 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 805753508 314 FIRQGCLQKYSRKGFQQRMFFLFSDILLYTFRTQQStQCFRVHGQLPLKGMKIRESDNKTGSDYAFMIDAQGNQSLTVAA 393
Cdd:cd01225    3 HMSQVAVQNTGCQEKKERYFLLFPHVLLMLSASPRM-SGFIYEGKLPLTGISVNRLEDTEGIKNAFEISGPLIERIVVIC 81

                         90
                 ....*....|....*..
gi 805753508 394 SNEEEKERWLEDLTQAI 410
Cdd:cd01225   82 NSQQDQQEWLEHLQQQT 98

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 4 pleckstrin homology (PH) domain, C-terminus, in insect and related arthropods; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. This cd contains insects, crustaceans, and chelicerates. 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 805753508 481 LSGFLLRKFKNSNGWQKLWVVF-TNFCLFFYKSHRDDFPLASLPLLGYTVTTPSEKDGI------NKDFVFKLQFKSHVY 553
Cdd:cd13238    1 LSGYLKLKTNGRKTWSRRWFALqPDFVLYSYKSQEDKLPLTATPVPGFLVTLLEKGSAVdplndpKRPRTFKMFHVKKSY 80

                         90
                 ....*....|....
gi 805753508 554 FFRAESDYTFGRWI 567
Cdd:cd13238   81 YFQANDGDEQKKWV 94

Pleckstrin homology (PH) domain containing, family D (with coiled-coil domains) member 1 PH domain; Human PLEKHD1 (also called UPF0639, pleckstrin homology domain containing, family D (with M protein repeats) member 1) is a single transcript and contains a single PH domain. PLEKHD1 is conserved in human, chimpanzee, , dog, cow, mouse, chicken, zebrafish, and Caenorhabditis elegans. 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 805753508 330 QRMFFLFSD-ILLY----TFRTQQSTQCFRVH--GQLPLKGMKIrESDNKTGSDYAFMID-AQGNQSLTVAASNEEEKER 401
Cdd:cd13281   31 SKRFFIIKEgFLLYysesEKKDFEKTRHFNIHpkGVIPLGGCSI-EAVEDPGKPYAISIShSDFKGNIILAADSEFEQEK 109

                 ....*...
gi 805753508 402 WLEDLTQA 409
Cdd:cd13281  110 WLDMLRES 117

SH3 domain-binding protein 2 Pleckstrin homology (PH) domain; SH3BP2 (the gene that encodes the adaptor protein 3BP2), HD, ITU, IT10C3, and ADD1 are located near the Huntington's Disease Gene on Human Chromosome 4pl6.3. SH3BP2 lies in a region that is often missing in individuals with Wolf-Hirschhorn syndrome (WHS). Gain of function mutations in SH3BP2 causes enhanced B-cell antigen receptor (BCR)-mediated activation of nuclear factor of activated T cells (NFAT), resulting in a rare, genetic disorder called cherubism. This results in an increase in the signaling complex formation with Syk, phospholipase C-gamma2 (PLC-gamma2), and Vav1. It was recently discovered that Tankyrase regulates 3BP2 stability through ADP-ribosylation and ubiquitylation by the E3-ubiquitin ligase. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the Src, Syk, and Vav signaling pathways. SH3BP2 is also a potential negative regulator of the abl oncogene. 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 805753508 482 SGFLLRK---FKNSNGWQKLWVVFTNFCLFFYKSHRDDFPLASLPLLGYTVTTPSEKdGINKDFVFKL---QFKSHVYFF 555
Cdd:cd13308   12 SGTLTKKggsQKTLQNWQLRYVIIHQGCVYYYKNDQSAKPKGVFSLNGYNRRAAEER-TSKLKFVFKIihlSPDHRTWYF 90

                         90       100
                 ....*....|....*....|...
gi 805753508 556 RAESDYTFGRWIEVIRSATQQSH 578
Cdd:cd13308   91 AAKSEDEMSEWMEYIRREIDHYC 113

Alsin Pleckstrin homology (PH) domain; The ALS2 gene encodes alsin, a GEF, that has dual specificity for Rac1 and Rab5 GTPases. Alsin mutations in the form of truncated proteins are responsible for motor function disorders including juvenile-onset amyotrophic lateral sclerosis, familial juvenile primary lateral sclerosis, and infantile-onset ascending hereditary spastic paralysis. The alsin protein is widely expressed in the developing CNS including neurons of the cerebral cortex, brain stem, spinal cord, and cerebellum. Alsin contains a regulator of chromosome condensation 1 (RCC1) domain, a Rho guanine nucleotide exchanging factor (RhoGEF) domain, a PH domain, a Membrane Occupation and Recognition Nexus (MORN), a vacuolar protein sorting 9 (Vps9) domain, and a Dbl homology (DH) domain. Alsin interacts with Rab5 through its Vps9 domain and through this interaction modulates early endosome fusion and trafficking. The GEF activity of alsin towards Rab5 is regulated by Rac1 function. The GEF activity of alsin for Rac1 occurs via its DH domain and this interaction plays a role in promoting spinal motor neuron survival via multiple Rac-dependent signaling pathways. 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 805753508 312 RRFIRQGC---LQKYSRKGFQQRMFFLFSDILLytfRTQQSTqcfrvHGQLPLKGMKIRESDNKTGSDYAFMIDAQgNQS 388
Cdd:cd13269    8 RRLIRESStrpLTLQNAGRFSSHWFILFNDALV---HAQFST-----HHIFPLATLWVEPIPDEDSGQNALKITTP-EES 78

                         90       100
                 ....*....|....*....|....*
gi 805753508 389 LTVAASNEEEKERWLEDLTQAIAQA 413
Cdd:cd13269   79 FTLVASTPQEKAEWLRAINQAIDQA 103

Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain; CNK family members function as protein scaffolds, regulating the activity and the subcellular localization of RAS activated RAF. There is a single CNK protein present in Drosophila and Caenorhabditis elegans in contrast to mammals which have 3 CNK proteins (CNK1, CNK2, and CNK3). All of the CNK members contain a sterile a motif (SAM), a conserved region in CNK (CRIC) domain, and a PSD-95/DLG-1/ZO-1 (PDZ) domain, and a PH domain. A CNK2 splice variant CNK2A also has a PDZ domain-binding motif at its C terminus and Drosophila CNK (D-CNK) also has a domain known as the Raf-interacting region (RIR) that mediates binding of the Drosophila Raf kinase. This cd contains CNKs from insects, spiders, mollusks, and nematodes. 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 805753508 481 LSGFLLRKFKNSNG---WQKLWVVFTNFCLFFYKSHRDDFPLASLPLLGYTVTTPSEKDgiNKDFVFKLQFKSHVYFFRA 557
Cdd:cd13326    1 YQGWLYQRRRKGKGggkWAKRWFVLKGSNLYGFRSQESTKADCVIFLPGFTVSPAPEVK--SRKYAFKVYHTGTVFYFAA 78

                         90
                 ....*....|...
gi 805753508 558 ESDYTFGRWIEVI 570
Cdd:cd13326   79 ESQEDMKKWLDLL 91

Human Oxysterol binding protein and OSBP-related protein 4 Pleckstrin homology (PH) domain; Human OSBP is proposed to function is sterol-dependent regulation of ERK dephosphorylation and sphingomyelin synthesis as well as modulation of insulin signaling and hepatic lipogenesis. It contains a N-terminal PH domain, a FFAT motif (two phenylalanines in an acidic tract), and a C-terminal OSBP-related domain. OSBPs and Osh1p PH domains specifically localize to the Golgi apparatus in a PtdIns4P-dependent manner. ORP4 is proposed to function in Vimentin-dependent sterol transport and/or signaling. Human ORP4 has 2 forms, a long (ORP4L) and a short (ORP4S). ORP4L contains a N-terminal PH domain, a FFAT motif (two phenylalanines in an acidic tract), and a C-terminal OSBP-related domain. ORP4S is truncated and contains only an OSBP-related domain. Oxysterol binding proteins are a multigene family that is conserved in yeast, flies, worms, mammals and plants. They all contain a C-terminal oxysterol binding domain, and most contain an N-terminal PH domain. OSBP PH domains bind to membrane phosphoinositides and thus likely play an important role in intracellular targeting. They are members of the oxysterol binding protein (OSBP) family which includes OSBP, OSBP-related proteins (ORP), Goodpasture antigen binding protein (GPBP), and Four phosphate adaptor protein 1 (FAPP1). They have a wide range of purported functions including sterol transport, cell cycle control, pollen development and vessicle transport from Golgi recognize both PI lipids and ARF proteins. 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 805753508 316 RQGCLQKYSR--KGFQQRMFFLfSDILLYTFRTQQ--STQCfrvHGQLPLKGMKIRESDNKTgsdyaFMIDAQGNQSLTV 391
Cdd:cd13284    1 MKGWLLKWTNyiKGYQRRWFVL-SNGLLSYYRNQAemAHTC---RGTINLAGAEIHTEDSCN-----FVISNGGTQTFHL 71

                         90       100
                 ....*....|....*....|..
gi 805753508 392 AASNEEEKERWLEDLTQAIAQA 413
Cdd:cd13284   72 KASSEVERQRWVTALELAKAKA 93

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. 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 805753508 482 SGFLLR---KFKNsngWQKLWVVFTNFCLFFYKSHRDDF--PLASLPLLGYTVTTPSEKDGinkdfVFKLQFKSHVYFFR 556
Cdd:cd13282    2 AGYLTKlggKVKT---WKRRWFVLKNGELFYYKSPNDVIrkPQGQIALDGSCEIARAEGAQ-----TFEIVTEKRTYYLT 73

                         90
                 ....*....|....*..
gi 805753508 557 AESDYTFGRWIEVIRSA 573
Cdd:cd13282   74 ADSENDLDEWIRVIQNV 90

Arabidopsis thaliana Pleckstrin homolog (PH) 1 (AtPH1) PH domain; AtPH1 is expressed in all plant tissue and is proposed to be the plant homolog of human pleckstrin. Pleckstrin consists of two PH domains separated by a linker region, while AtPH has a single PH domain with a short N-terminal extension. AtPH1 binds PtdIns3P specifically and is thought to be an adaptor molecule since it has no obvious catalytic functions. 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 805753508 495 WQKLWVVFTNFCLFFYKShrDDFPLASLP----LLGYTVTTPSEKDGINKDFVFKLQFKSHVYFFRAESDYTFGRWIEVI 570
Cdd:cd13276   15 WRRRWFVLKQGKLFWFKE--PDVTPYSKPrgviDLSKCLTVKSAEDATNKENAFELSTPEETFYFIADNEKEKEEWIGAI 92

                         90
                 ....*....|..
gi 805753508 571 RSATQQSHVSLN 582
Cdd:cd13276   93 GRAIVKHSRSVT 104

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 1, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. However, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells and while FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. They also reciprocally regulated cell motility in inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration while FGD3 inhibited it. FGD1 and FGD3 therefore play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

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gi 805753508 314 FIRQGCLQKYSRKG--FQQRMFFLFSDILLYTF-RTQQSTQCFRVHGQLPLKGMKIRESDNKTGSDyAFMIDAQgNQSLT 390
Cdd:cd01219    1 LIKEGHILKLSAKNgtTQDRYLILFNDRLLYCVpKLRLIGQKFSVRARIDVEGMELKESSSLNLPR-TFLVSGK-QRSLE 78

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gi 805753508 391 VAASNEEEKERWLEDLTQAI 410
Cdd:cd01219   79 LQARTEEEKKDWIQAIQATI 98