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 2462578963 708 VENQLSGYLLRKFKNSHGWQKLWVVFTNFCLFFYKTHQDDYPLASLPLLGYSVSIPREADGIHKDYVFKLQFKSHVYFFR 787
Cdd:cd13235     1 VENQMSGYLLRKFKNSNGWQKLWVVFTNFCLFFYKSHQDEFPLASLPLLGYSVGLPSEADNIDKDYVFKLQFKSHVYFFR 80

                          90
                  ....*....|....*...
gi 2462578963 788 AESKYTFERWMEVIQGAS 805
Cdd:cd13235    81 AESEYTFERWMEVIRSAT 98

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 2462578963 522 LIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSKGVAGTSHFRIRGLLPLQGMLlivldppVEESDNEWSVPHCF 601
Cdd:cd01220     1 LVQPGREFIREGCLQKLSKKGLQQRMFFLFSDVLLYTSRSPTPSLQFKVHGQLPLRGLM-------VEESEPEWGVAHCF 73

                          90       100       110
                  ....*....|....*....|....*....|....
gi 2462578963 602 TIYAAQKTIVVAASTRLEKEKWMLDLNSAIQAAK 635
Cdd:cd01220    74 TIYGGNRALTVAASSEEEKERWLEDLQRAIDAAK 107

FERM adjacent (FA); This region is found adjacent to Band 4.1 / FERM domains (pfam00373) in a subset of FERM containing protein. The region has been hypothesized to play a role in regulatory adaptation, based on similarity to other protein kinase substrates.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2462578963 106 VFFSRGSSFRYSGRTQKQLVDYFKDSGMKRIPYERRHSKTHTS 148
Cdd:pfam08736   1 KFFSLGSKFRYSGRTQKQTVEDSSEILRPQPEFERSPSKRYPS 43

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 2462578963 708 VENQLSGYLLRKFKNSHGWQKLWVVFTNFCLFFYKTHQDDYPLASLPLLGYSVSIPREADGIHKDYVFKLQFKSHVYFFR 787
Cdd:cd13235     1 VENQMSGYLLRKFKNSNGWQKLWVVFTNFCLFFYKSHQDEFPLASLPLLGYSVGLPSEADNIDKDYVFKLQFKSHVYFFR 80

                          90
                  ....*....|....*...
gi 2462578963 788 AESKYTFERWMEVIQGAS 805
Cdd:cd13235    81 AESEYTFERWMEVIRSAT 98

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 2462578963 522 LIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSKGVAGTSHFRIRGLLPLQGMLlivldppVEESDNEWSVPHCF 601
Cdd:cd01220     1 LVQPGREFIREGCLQKLSKKGLQQRMFFLFSDVLLYTSRSPTPSLQFKVHGQLPLRGLM-------VEESEPEWGVAHCF 73

                          90       100       110
                  ....*....|....*....|....*....|....
gi 2462578963 602 TIYAAQKTIVVAASTRLEKEKWMLDLNSAIQAAK 635
Cdd:cd01220    74 TIYGGNRALTVAASSEEEKERWLEDLQRAIDAAK 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 2462578963  312 IVKEILATERTYLKDLEVITVWFRSAVVKE-DAMPATLMTLLFSNIDPIYEFHRGFLREVEQRLALWEGPskahtkgsHQ 390
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKElKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDS--------VE 72

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963  391 RIGDILLRNMRQLKEFTSYFQRHDEVLTELEKATKRcKKLEAVYKEFELQKVCY-LPLNTFLLKPIQRLLHYRLLLRRLC 469
Cdd:smart00325  73 RIGDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKN-PRFQKFLKEIESSPQCRrLTLESLLLKPVQRLTKYPLLLKELL 151

                          170       180
                   ....*....|....*....|....*...
gi 2462578963  470 GHYSPGHHDYADCHDALKAITEVTTTLQ 497
Cdd:smart00325 152 KHTPEDHEDREDLKKALKAIKELANQVN 179

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 2462578963 312 IVKEILATERTYLKDLEVITVWFRSAVVKEDAMPATLMTLLFSNIDPIYEFHRGFLreVEQRLALWEgpskahtkgSHQR 391
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLKEWI---------SIQR 69

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963 392 IGDILLRNMRQLKEFTSYFQRHDEVLTELEKATKRCKKLEAVYKEFELQKVCY-LPLNTFLLKPIQrllhyrlllrrLCG 470
Cdd:pfam00621  70 IGDIFLKFAPGFKVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRgLDLNSFLIKPVQ-----------RIP 138

                         170       180       190
                  ....*....|....*....|....*....|....*
gi 2462578963 471 HY-----------SPGHHDYADCHDALKAITEVTT 494
Cdd:pfam00621 139 RYplllkellkhtPPDHPDYEDLKKALEAIKEVAK 173

FERM adjacent (FA); This region is found adjacent to Band 4.1 / FERM domains (pfam00373) in a subset of FERM containing protein. The region has been hypothesized to play a role in regulatory adaptation, based on similarity to other protein kinase substrates.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2462578963 106 VFFSRGSSFRYSGRTQKQLVDYFKDSGMKRIPYERRHSKTHTS 148
Cdd:pfam08736   1 KFFSLGSKFRYSGRTQKQTVEDSSEILRPQPEFERSPSKRYPS 43

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963 713 SGYLLRKFK-NSHGWQKLWVVFTNFCLFFYK---THQDDYPLASLPLLGYSVSIPREADGIHKDYVFKL----QFKSHVY 784
Cdd:pfam00169   4 EGWLLKKGGgKKKSWKKRYFVLFDGSLLYYKddkSGKSKEPKGSISLSGCEVVEVVASDSPKRKFCFELrtgeRTGKRTY 83

                          90       100
                  ....*....|....*....|..
gi 2462578963 785 FFRAESKYTFERWMEVIQGASS 806
Cdd:pfam00169  84 LLQAESEEERKDWIKAIQSAIR 105

DNA translocase FtsK; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963  121 QKQLVDYFKDSGMKRIPYERRHSKTHTSVR---ALTADLPKQSISFPEGLRTPASPSSANAF----YSLSP--------- 184
Cdd:PRK10263   661 QDELARQFAQTQQQRYGEQYQHDVPVNAEDadaAAEAELARQFAQTQQQRYSGEQPAGANPFslddFEFSPmkallddgp 740

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963  185 --STLVPSGLPEFKDSSSSLTDPQVSYVKSPAAERRSGAVAGGPDTPSAQ---PLGPPALQPGPGLSTK--SPQPSPSSR 257
Cdd:PRK10263   741 hePLFTPIVEPVQQPQQPVAPQQQYQQPQQPVAPQPQYQQPQQPVAPQPQyqqPQQPVAPQPQYQQPQQpvAPQPQYQQP 820

                          170       180       190
                   ....*....|....*....|....*....|....
gi 2462578963  258 KSPLSLSPAFQVPLGP-AEQGSSPLLSPVLSDAG 290
Cdd:PRK10263   821 QQPVAPQPQYQQPQQPvAPQPQDTLLHPLLMRNG 854

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 2462578963 708 VENQLSGYLLRKFKNSHGWQKLWVVFTNFCLFFYKTHQDDYPLASLPLLGYSVSIPREADGIHKDYVFKLQFKSHVYFFR 787
Cdd:cd13235     1 VENQMSGYLLRKFKNSNGWQKLWVVFTNFCLFFYKSHQDEFPLASLPLLGYSVGLPSEADNIDKDYVFKLQFKSHVYFFR 80

                          90
                  ....*....|....*...
gi 2462578963 788 AESKYTFERWMEVIQGAS 805
Cdd:cd13235    81 AESEYTFERWMEVIRSAT 98

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 2462578963 522 LIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSKGVAGTSHFRIRGLLPLQGMLlivldppVEESDNEWSVPHCF 601
Cdd:cd01220     1 LVQPGREFIREGCLQKLSKKGLQQRMFFLFSDVLLYTSRSPTPSLQFKVHGQLPLRGLM-------VEESEPEWGVAHCF 73

                          90       100       110
                  ....*....|....*....|....*....|....
gi 2462578963 602 TIYAAQKTIVVAASTRLEKEKWMLDLNSAIQAAK 635
Cdd:cd01220    74 TIYGGNRALTVAASSEEEKERWLEDLQRAIDAAK 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 2462578963  312 IVKEILATERTYLKDLEVITVWFRSAVVKE-DAMPATLMTLLFSNIDPIYEFHRGFLREVEQRLALWEGPskahtkgsHQ 390
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKElKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDS--------VE 72

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963  391 RIGDILLRNMRQLKEFTSYFQRHDEVLTELEKATKRcKKLEAVYKEFELQKVCY-LPLNTFLLKPIQRLLHYRLLLRRLC 469
Cdd:smart00325  73 RIGDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKN-PRFQKFLKEIESSPQCRrLTLESLLLKPVQRLTKYPLLLKELL 151

                          170       180
                   ....*....|....*....|....*...
gi 2462578963  470 GHYSPGHHDYADCHDALKAITEVTTTLQ 497
Cdd:smart00325 152 KHTPEDHEDREDLKKALKAIKELANQVN 179

FERM domain C-lobe of Protein tyrosine phosphatase non-receptor proteins 3 and 4 (PTPN4 and PTPN3); PTPN4 (also called PTPMEG, protein tyrosine phosphatase, megakaryocyte) is a cytoplasmic protein-tyrosine phosphatase (PTP) thought to play a role in cerebellar function. PTPMEG-knockout mice have impaired memory formation and cerebellar long-term depression. PTPN3/PTPH1 is a membrane-associated PTP that is implicated in regulating tyrosine phosphorylation of growth factor receptors, p97 VCP (valosin-containing protein, or Cdc48 in Saccharomyces cerevisiae), and HBV (Hepatitis B Virus) gene expression; it is mutated in a subset of colon cancers. PTPMEG and PTPN3/PTPH1 contains a N-terminal FERM domain, a middle PDZ domain, and a C-terminal phosphatase domain. PTP1/Tyrosine-protein phosphatase 1 from nematodes and a FERM_C repeat 1 from Tetraodon nigroviridis are also included in this cd. The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963   1 MYGIRFHMASDREGTKIQLAVSHMGVLVFQGTTKINTFNWSKVRKLSFKRKRFLIKLHPEVHGPYQDTLEFLLGSRDECK 80
Cdd:cd13189     1 LYGVELHSARDSNNLELQIGVSSAGILVFQNGIRINTFPWSKIVKISFKRKQFFIQLRREPNESRDTILGFNMLSYRACK 80

                          90
                  ....*....|....*
gi 2462578963  81 NFWKICVEYHTFFRL 95
Cdd:cd13189    81 NLWKSCVEHHTFFRL 95

FERM domain C-lobe of Protein 4.1 family; The protein 4.1 family includes four well-defined members: erythroid protein 4.1 (4.1R), the best known and characterized member, 4.1G (general), 4.1N (neuronal), and 4.1 B (brain). The less well understood 4.1O/FRMD3 is not a true member of this family and is not included in this hierarchy. Besides three highly conserved domains, FERM, SAB (spectrin and actin binding domain) and CTD (C-terminal domain), the proteins from this family contain several unique domains: U1, U2 and U3. FERM domains like other members of the FERM domain superfamily have a cloverleaf architecture with three distinct lobes: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The brain is a particularly rich source of protein 4.1 isoforms. The various 4.1R, 4.1G, 4.1N, and 4.1B mRNAs are all expressed in distinct patterns within the brain. It is likely that 4.1 proteins play important functional roles in the brain including motor coordination and spatial learning, postmitotic differentiation, and synaptic architecture and function. In addition they are found in nonerythroid, nonneuronal cells where they may play a general structural role in nuclear architecture and/or may interact with splicing factors. The FERM C domain is the third structural domain within the FERM domain. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963   2 YGIRFHMASDREGTKIQLAVSHMGVLVFQGTTKINTFNWSKVRKLSFKRKRFLIKLHPEVHGPYQDTLEFLLGSRDECKN 81
Cdd:cd13184     1 YGVDLHPAKDSEGVDIMLGVCSSGLLVYRDRLRINRFAWPKVLKISYKRNNFYIKIRPGEFEQYETTIGFKLPNHRAAKR 80

                          90
                  ....*....|....
gi 2462578963  82 FWKICVEYHTFFRL 95
Cdd:cd13184    81 LWKVCVEHHTFFRL 94

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 2462578963 504 ENLQKLTELQRDLVGIEN-LIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSkGVAGTSHFRIRGLLPLQGMLli 582
Cdd:cd01218     4 ANRRRIAAVESCFGGSGQpLVKPGRVLVGEGVLTKVCRKKPKPRQFFLFNDILVYGS-IVINKKKYNKQRIIPLEDVK-- 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 2462578963 583 vldppVEESDNEWSVPHCFTIYAAQKTIVVAASTRLEKEKWMLDLN 628
Cdd:cd01218    81 -----IEDLEDTGELKNGWQIISPKKSFVVYAATATEKSEWMDHIN 121

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 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 2462578963 516 LVGIENLIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSKGVAGTshFRIRGLLPLQGMLliVLDPPVEESDNEw 595
Cdd:cd15793     1 LNGHHEIVQPGRVFLKEGTLMKLSRKVMQPRMFFLFNDALLYTTPVQSGM--YKLNNMLSLAGMK--VSKPSQEAYQNE- 75

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 2462578963 596 svphcFTIYAAQKTIVVAASTRLEKEKWMLDLNSAIQ 632
Cdd:cd15793    76 -----LNIESVERSFILSASSATERDEWLEAISRAIE 107

FERM domain C-lobe; The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963   3 GIRFHMA--SDREGTKIQLAVSHMGVLVFQGTTK--INTFNWSKVRKLSFKR-KRFLIKLHPEVHgpyQDTLEFLLGSRd 77
Cdd:cd00836     1 GVEFFPVkdKSKKGSPIILGVNPEGISVYDELTGqpLVLFPWPNIKKISFSGaKKFTIVVADEDK---QSKLLFQTPSR- 76

                          90
                  ....*....|....*..
gi 2462578963  78 ECKNFWKICVEYHTFFR 94
Cdd:cd00836    77 QAKEIWKLIVGYHRFLL 93

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 2462578963 712 LSGYLLRKFKNSHGWQKLWVVFTNFCLFFYKTHQDDYPLASLPLLGYSVSIPREADGIHKDYVFKLQFKSHVYF-FRAES 790
Cdd:cd13237     1 MSGYLQRRKKSKKSWKRLWFVLKDKVLYTYKASEDVVALESVPLLGFTVVTIDESFEEDESLVFQLLHKGQLPIiFRADD 80

                          90
                  ....*....|.
gi 2462578963 791 KYTFERWMEVI 801
Cdd:cd13237    81 AETAQRWIEAL 91

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 2462578963  529 FIREGCLHKLT---KKGLQQRMFFLFSDMLLYTSKGVAGTShFRIRGLLPLQGMllIVLDPPVEESDNEwsvPHCFTI-Y 604
Cdd:smart00233   1 VIKEGWLYKKSgggKKSWKKRYFVLFNSTLLYYKSKKDKKS-YKPKGSIDLSGC--TVREAPDPDSSKK---PHCFEIkT 74

                           90       100
                   ....*....|....*....|....*...
gi 2462578963  605 AAQKTIVVAASTRLEKEKWMLDLNSAIQ 632
Cdd:smart00233  75 SDRKTLLLQAESEEEREKWVEALRKAIA 102

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 2462578963 722 NSHGWQKLWVVFTN---FCLFFYKTHQDDYPLASLPLLGYSVSIPREADGIHKDYVFKLQFKSHVYFFRAESKYTFERWM 798
Cdd:cd13236    19 KGKTWQKVWCVIPRtepLVLYLYGAPQDVRAQRTIPLPGCEVTVPPPEERLDGRHVFKLSQSKQSHYFSAESEELQQRWL 98

                  ....*..
gi 2462578963 799 EVIQGAS 805
Cdd:cd13236    99 EALSRAA 105

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578963 713 SGYLLRKFK-NSHGWQKLWVVFTNFCLFFYK---THQDDYPLASLPLLGYSVSIPREADGIHKDYVFKL----QFKSHVY 784
Cdd:pfam00169   4 EGWLLKKGGgKKKSWKKRYFVLFDGSLLYYKddkSGKSKEPKGSISLSGCEVVEVVASDSPKRKFCFELrtgeRTGKRTY 83

                          90       100
                  ....*....|....*....|..
gi 2462578963 785 FFRAESKYTFERWMEVIQGASS 806
Cdd:pfam00169  84 LLQAESEEERKDWIKAIQSAIR 105

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 2462578963 712 LSGYLLRK-FKNSHGWQKLWVVFTNFCLFFYKTHQDD--YPLASLPLLGYSVsiPREADGIHKDYVFKLQFKSH-VYFFR 787
Cdd:cd00821     1 KEGYLLKRgGGGLKSWKKRWFVLFEGVLLYYKSKKDSsyKPKGSIPLSGILE--VEEVSPKERPHCFELVTPDGrTYYLQ 78

                          90
                  ....*....|....
gi 2462578963 788 AESKYTFERWMEVI 801
Cdd:cd00821    79 ADSEEERQEWLKAL 92

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 1-4 and similar proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). 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. They play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway. 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 2462578963 530 IREGCLHKLTKKG--LQQRMFFLFSDMLLYTS-KGVAGTSHFRIRGLLPLQGMllivldpPVEESDNEwSVPHCFTIYAA 606
Cdd:cd13388     2 IKEGKILKISARNgdTQERYLFLFNDMLLYCSpRLRLIGQKYKVRARFDVDGM-------QVLEGDNL-ETPHTFYVRGK 73

                          90
                  ....*....|....*...
gi 2462578963 607 QKTIVVAASTRLEKEKWM 624
Cdd:cd13388    74 QRSLELQASTQEEKAEWV 91

Fungal proteins Pleckstrin homology (PH) domain, repeat 1; The functions of these fungal proteins are unknown, but they all contain 2 PH domains. This cd represents 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 2462578963 712 LSGYLLRKFKNSHGWQKLWVVFTNFCLFFYKTHQDDYPLASLPLLG-YSVSIPREAdgiHKDYVFKLQFKSHVYFFRAES 790
Cdd:cd13298     8 KSGYLLKRSRKTKNWKKRWVVLRPCQLSYYKDEKEYKLRRVINLSElLAVAPLKDK---KRKNVFGIYTPSKNLHFRATS 84

                          90
                  ....*....|....*..
gi 2462578963 791 KYTFERWMEVIQGASSS 807
Cdd:cd13298    85 EKDANEWVEALREEFRL 101

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 2462578963 712 LSGYLLRKFKNSHGWQKLWVVF-TNFCLFFYKTHQDDYPLASLPLLGYSVSIPREADGI------HKDYVFKLQFKSHVY 784
Cdd:cd13238     1 LSGYLKLKTNGRKTWSRRWFALqPDFVLYSYKSQEDKLPLTATPVPGFLVTLLEKGSAVdplndpKRPRTFKMFHVKKSY 80

                          90
                  ....*....|....
gi 2462578963 785 FFRAESKYTFERWM 798
Cdd:cd13238    81 YFQANDGDEQKKWV 94

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 2462578963 713 SGYLLR---KFKNshgWQKLWVVFTNFCLFFYKtHQDDY---PLASLPLLGYSVSIPreADGIHkdyVFKLQFKSHVYFF 786
Cdd:cd13282     2 AGYLTKlggKVKT---WKRRWFVLKNGELFYYK-SPNDVirkPQGQIALDGSCEIAR--AEGAQ---TFEIVTEKRTYYL 72

                          90
                  ....*....|....*...
gi 2462578963 787 RAESKYTFERWMEVIQGA 804
Cdd:cd13282    73 TADSENDLDEWIRVIQNV 90