Pleckstrin homology domain-containing family G members 1, 2, and 3 pleckstrin homology (PH) domain; PLEKHG1 (also called ARHGEF41), PLEKHG2 (also called ARHGEF42 or CLG/common-site lymphoma/leukemia guanine nucleotide exchange factor2), and PLEKHG3 (also called ARHGEF43) have RhoGEF DH/double-homology domains in tandem with a PH domain which is involved in phospholipid binding. They function as a guanine nucleotide exchange factor (GEF) and are involved in the regulation of Rho protein signal transduction. Mutations in PLEKHG1 have been associated panic disorder (PD), an anxiety disorder characterized by panic attacks and anticipatory anxiety. 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 1958785984  274 EVVEDAIDTMTCVAWYINDMKRRHEHAVRLQEIQSLLINWKGPDLTTYGELVLEATFRVHRVRNERTFFLFDKILLITKK 353
Cdd:cd13243      2 SVVEEALDTMTQVAWHINDMKRKHEHAVRVQEIQSLLDGWEGPELTTYGDLVLEGTFRMAGAKNERLLFLFDKMLLITKK 81

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958785984  354 RGDH-FVYKGHIPCSSLMLIES-TRDSLCFTVTHYKHSKQQYSIQAKTVEEKRSWTHHIKRLILEN 417
Cdd:cd13243     82 REDGiLQYKTHIMCSNLMLSESiPKEPLSFQVLPFDNPKLQYTLQAKNQEQKRLWTQEIKRLILEN 147

Pleckstrin homology domain-containing family G members 1, 2, and 3 pleckstrin homology (PH) domain; PLEKHG1 (also called ARHGEF41), PLEKHG2 (also called ARHGEF42 or CLG/common-site lymphoma/leukemia guanine nucleotide exchange factor2), and PLEKHG3 (also called ARHGEF43) have RhoGEF DH/double-homology domains in tandem with a PH domain which is involved in phospholipid binding. They function as a guanine nucleotide exchange factor (GEF) and are involved in the regulation of Rho protein signal transduction. Mutations in PLEKHG1 have been associated panic disorder (PD), an anxiety disorder characterized by panic attacks and anticipatory anxiety. 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 1958785984  274 EVVEDAIDTMTCVAWYINDMKRRHEHAVRLQEIQSLLINWKGPDLTTYGELVLEATFRVHRVRNERTFFLFDKILLITKK 353
Cdd:cd13243      2 SVVEEALDTMTQVAWHINDMKRKHEHAVRVQEIQSLLDGWEGPELTTYGDLVLEGTFRMAGAKNERLLFLFDKMLLITKK 81

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958785984  354 RGDH-FVYKGHIPCSSLMLIES-TRDSLCFTVTHYKHSKQQYSIQAKTVEEKRSWTHHIKRLILEN 417
Cdd:cd13243     82 REDGiLQYKTHIMCSNLMLSESiPKEPLSFQVLPFDNPKLQYTLQAKNQEQKRLWTQEIKRLILEN 147

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 1958785984   118 VVREIVETERMYVQDLRSIVEDYLLKIIDTPGLLKPEQVSALFGNIESIYALNSQLLRDLDSC----NSDPVAVASCFVE 193
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKLLSPNELETLFGNIEEIYEFHRDFLDELEERieewDDSVERIGDVFLK 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958785984   194 RSQEFDIYTQYCNNYPNSVAALTECMQDKQQAKFFRDRQELLQH-SLPLGSYLLKPVQRILKYHLLLQEIAKHFDEEEDG 272
Cdd:smart00325   81 LEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLKHTPEDHED 160

                           170       180
                    ....*....|....*....|
gi 1958785984   273 FEVVEDAIDTMTCVAWYIND 292
Cdd:smart00325  161 REDLKKALKAIKELANQVNE 180

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958785984   336 RNERTFFLFDKILLITKKRGDH--FVYKGHIPCSSLMLIESTRDSL-----CFTVTHykHSKQQYSIQAKTVEEKRSWTH 408
Cdd:smart00233   18 WKKRYFVLFNSTLLYYKSKKDKksYKPKGSIDLSGCTVREAPDPDSskkphCFEIKT--SDRKTLLLQAESEEEREKWVE 95

                    ....*.
gi 1958785984   409 HIKRLI 414
Cdd:smart00233   96 ALRKAI 101

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958785984  338 ERTFFLFDKILLITK--KRGDHFVYKGHIPCSSLMLIESTRDS-----LCFTV-THYKHSKQQYSIQAKTVEEKRSWTHH 409
Cdd:pfam00169   20 KRYFVLFDGSLLYYKddKSGKSKEPKGSISLSGCEVVEVVASDspkrkFCFELrTGERTGKRTYLLQAESEEERKDWIKA 99

                   ....*
gi 1958785984  410 IKRLI 414
Cdd:pfam00169  100 IQSAI 104

Pleckstrin homology domain-containing family G members 1, 2, and 3 pleckstrin homology (PH) domain; PLEKHG1 (also called ARHGEF41), PLEKHG2 (also called ARHGEF42 or CLG/common-site lymphoma/leukemia guanine nucleotide exchange factor2), and PLEKHG3 (also called ARHGEF43) have RhoGEF DH/double-homology domains in tandem with a PH domain which is involved in phospholipid binding. They function as a guanine nucleotide exchange factor (GEF) and are involved in the regulation of Rho protein signal transduction. Mutations in PLEKHG1 have been associated panic disorder (PD), an anxiety disorder characterized by panic attacks and anticipatory anxiety. 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 1958785984  274 EVVEDAIDTMTCVAWYINDMKRRHEHAVRLQEIQSLLINWKGPDLTTYGELVLEATFRVHRVRNERTFFLFDKILLITKK 353
Cdd:cd13243      2 SVVEEALDTMTQVAWHINDMKRKHEHAVRVQEIQSLLDGWEGPELTTYGDLVLEGTFRMAGAKNERLLFLFDKMLLITKK 81

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958785984  354 RGDH-FVYKGHIPCSSLMLIES-TRDSLCFTVTHYKHSKQQYSIQAKTVEEKRSWTHHIKRLILEN 417
Cdd:cd13243     82 REDGiLQYKTHIMCSNLMLSESiPKEPLSFQVLPFDNPKLQYTLQAKNQEQKRLWTQEIKRLILEN 147

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 1958785984   118 VVREIVETERMYVQDLRSIVEDYLLKIIDTPGLLKPEQVSALFGNIESIYALNSQLLRDLDSC----NSDPVAVASCFVE 193
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKLLSPNELETLFGNIEEIYEFHRDFLDELEERieewDDSVERIGDVFLK 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958785984   194 RSQEFDIYTQYCNNYPNSVAALTECMQDKQQAKFFRDRQELLQH-SLPLGSYLLKPVQRILKYHLLLQEIAKHFDEEEDG 272
Cdd:smart00325   81 LEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLKHTPEDHED 160

                           170       180
                    ....*....|....*....|
gi 1958785984   273 FEVVEDAIDTMTCVAWYIND 292
Cdd:smart00325  161 REDLKKALKAIKELANQVNE 180

Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958785984  298 EHAVRLQEIQSLLINWKGPDLTTYGELVLEATfRVHRVR----NERTFFLFDKILLITKK---RGDHFVYKGHIPcSSLM 370
Cdd:cd01224      2 ENLEKLAAWQSTVEGWEGEDLSDRSSELIHSG-ELTKISagraQERTFFLFDHQLVYCKKdllRRKNYIYKGRID-TDNM 79

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1958785984  371 LIESTRDSLCF----TVTH----YKHSKQQ-YSIQAKTVEEKRSW 406
Cdd:cd01224     80 EIEDLPDGKDDesgvTVKNawkiYNASKNKwYVLCAKSAEEKQRW 124

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1958785984  338 ERTFFLFDKILLITKKRGD-HFVYKGHIPCSSLMLIESTRDSL---CFTVTHYKHskQQYSIQAKTVEEKRSWTHHI 410
Cdd:cd00821     18 KRWFVLFEGVLLYYKSKKDsSYKPKGSIPLSGILEVEEVSPKErphCFELVTPDG--RTYYLQADSEEERQEWLKAL 92

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 1958785984   336 RNERTFFLFDKILLITKKRGDH--FVYKGHIPCSSLMLIESTRDSL-----CFTVTHykHSKQQYSIQAKTVEEKRSWTH 408
Cdd:smart00233   18 WKKRYFVLFNSTLLYYKSKKDKksYKPKGSIDLSGCTVREAPDPDSskkphCFEIKT--SDRKTLLLQAESEEEREKWVE 95

                    ....*.
gi 1958785984   409 HIKRLI 414
Cdd:smart00233   96 ALRKAI 101

Shape and Conjugation Deficiency 1 Pleckstrin homology (PH) domain; Fission yeast Scd1 is an exchange factor for Cdc42 and an effector of Ras1, the homolog of the human H-Ras. Scd2/Bem1 mediates Cdc42 activation by binding to Scd1/Cdc24 and to Cdc42. Ras1 regulates Scd1/Cdc24/Ral1, which is a putative guanine nucleotide exchange factor for Cdc42, a member of the Rho family of Ras-like proteins. Cdc42 then activates the Shk1/Orb2 protein kinase. Scd1 interacts with Klp5 and Klp6 kinesins to mediate cytokinesis. 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 1958785984  294 KRRHEHAVRLQEIQSLLINWKGPDLTTYGELVLEATFRVHRVRNERTF--FLFDKILLITK 352
Cdd:cd13246      1 QRRAENQQVVDDLKARVEDWKGHSLDSFGELLLHDTFTVRKDDSEREYhvYLFERILLCCK 61

Vav pleckstrin homology (PH) domain; Vav acts as a guanosine nucleotide exchange factor (GEF) for Rho/Rac proteins. They control processes including T cell activation, phagocytosis, and migration of cells. The Vav subgroup of Dbl GEFs consists of three family members (Vav1, Vav2, and Vav3) in mammals. Vav1 is preferentially expressed in the hematopoietic system, while Vav2 and Vav3 are described by broader expression patterns. Mammalian Vav proteins consist of a calponin homology (CH) domain, an acidic region, a catalytic Dbl homology (DH) domain, a PH domain, a zinc finger cysteine rich domain (C1/CRD), and an SH2 domain, flanked by two SH3 domains. In invertebrates such as Drosophila and C. elegans, Vav is missing the N-terminal SH3 domain. The DH domain is involved in RhoGTPase recognition and selectivity and stimulates the reorganization of the switch regions for GDP/GTP exchange. The PH domain is implicated in directing membrane localization, allosteric regulation of guanine nucleotide exchange activity, and as a phospholipid- dependent regulator of GEF activity. Vavs bind RhoGTPases including Rac1, RhoA, RhoG, and Cdc42, while other members of the GEF family are specific for a single RhoGTPase. This promiscuity is thought to be a result of its CRD. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.polarized. PH domains also have diverse functions. They are often involved in targeting proteins to the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958785984  307 QSLLINWKGPDLTTYGELVLEATFRV-----HRVRNeRTFFLFDKILLITKK-RGDHFVYKGHIPCSS------LMLIES 374
Cdd:cd01223      2 IQDLIENLNESLADYGRLQIDGELKIkshedQKKKD-RYAFLFDKVLLICKSlRGDQYEYKEIINLSEyrieddPSRRTL 80

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1958785984  375 TRD---SLCFTVTHyKHSKQQYSIQAKTVEEKRSW 406
Cdd:cd01223     81 KRDkrwSYQFLLVH-KQGKTAYTLYAKTEELKKKW 114

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 1958785984  337 NERTFFLFDKILLITKKRGD---HFVYKGHIPCSSLMlIESTRDSL----CFTVThykHSKQQYSIQAKTVEEKRSWTHH 409
Cdd:cd01220     23 QQRMFFLFSDVLLYTSRSPTpslQFKVHGQLPLRGLM-VEESEPEWgvahCFTIY---GGNRALTVAASSEEEKERWLED 98

                   ....*
gi 1958785984  410 IKRLI 414
Cdd:cd01220     99 LQRAI 103