FERM domain C-lobe of FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins; 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 FRMD7(FERM domain containing 7). FARP1 and FARP2 are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. 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. These members are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. Other members in this family do not contain the DH domains such as the Human FERM domain containing protein 7 and Caenorhabditis elegans CFRM3, both of which have unknown functions. They contain an N-terminal FERM domain, a PH domain, followed by a FA (FERM adjacent) domain. 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 2462578961  172 EIARKLEMYGIRFHMASDREGTKIQLAVSHMGVLVFQGTTKINTFNWSKVRKLSFKRKRFLIKLHPEVHGPYQDTLEFLL 251
Cdd:cd13193      1 ETARRCELYGIRLHPAKDREGVKLNLAVAHMGILVFQGFTKINTFSWAKIRKLSFKRKRFLIKLHPEAYGSYKDTVEFSF 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|..
gi 2462578961  252 GSRDECKNFWKICVEYHTFFRLLDQPKPKA-KAVFFSRGSSF 292
Cdd:cd13193     81 ESRNECKSFWKKCIEHHAFFRCSEVPKPPSpKLRLFSRGSSF 122

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 2462578961  700 LIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSKGVAGTSHFRIRGLLPLQGMLlivldppVEESDNEWSVPHCF 779
Cdd:cd01220      1 LVQPGREFIREGCLQKLSKKGLQQRMFFLFSDVLLYTSRSPTPSLQFKVHGQLPLRGLM-------VEESEPEWGVAHCF 73

                           90       100       110
                   ....*....|....*....|....*....|....
gi 2462578961  780 TIYAAQKTIVVAASTRLEKEKWMLDLNSAIQAAK 813
Cdd:cd01220     74 TIYGGNRALTVAASSEEEKERWLEDLQRAIDAAK 107

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 2462578961  488 YFIVKEILATERTYLKDLEVITVWFRSAVVKEDA-MPATLMTLLFSNIDPIYEFHRGFLREVEQRLALWEGPskahtkgs 566
Cdd:cd00160      2 QEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLpLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKS-------- 73

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961  567 HQRIGDILLRNMRQLKEFTSYFQRHDEVLTELEKATKRCKKLEAVYKEFELQkVCYLPLNTFLLKPIQRLLHYRLLLRRL 646
Cdd:cd00160     74 GPRIGDVFLKLAPFFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLEKAESE-CGRLKLESLLLKPVQRLTKYPLLLKEL 152

                          170       180
                   ....*....|....*....|....*
gi 2462578961  647 CGHYSPGHHDYADCHDALKAITEVT 671
Cdd:cd00160    153 LKHTPDGHEDREDLKKALEAIKEVA 177

transcriptional regulator ICP4; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961  309 SGMKRIPYERRHSKTHTSVRALTADLPKQSISFPEGLRTPASPSSAnAFYSLSPSTLVPSGLPEFKDSSSSLTDPqvSYV 388
Cdd:PHA03307    74 GPGTEAPANESRSTPTWSLSTLAPASPAREGSPTPPGPSSPDPPPP-TPPPASPPPSPAPDLSEMLRPVGSPGPP--PAA 150

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961  389 KSPAAERRSGAVAGGPDTP------------SAQPLGPPALQPGPGLSTKSPQPSPSSRKSPLSLSPAFQVPLGP----- 451
Cdd:PHA03307   151 SPPAAGASPAAVASDAASSrqaalplsspeeTARAPSSPPAEPPPSTPPAAASPRPPRRSSPISASASSPAPAPGrsaad 230

                          170       180       190
                   ....*....|....*....|....*....|....*
gi 2462578961  452 -AEQGSSPLLSPVLSDAGGAGMD-CEEPRHKRVPA 484
Cdd:PHA03307   231 dAGASSSDSSSSESSGCGWGPENeCPLPRPAPITL 265

FERM domain C-lobe of FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins; 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 FRMD7(FERM domain containing 7). FARP1 and FARP2 are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. 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. These members are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. Other members in this family do not contain the DH domains such as the Human FERM domain containing protein 7 and Caenorhabditis elegans CFRM3, both of which have unknown functions. They contain an N-terminal FERM domain, a PH domain, followed by a FA (FERM adjacent) domain. 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 2462578961  172 EIARKLEMYGIRFHMASDREGTKIQLAVSHMGVLVFQGTTKINTFNWSKVRKLSFKRKRFLIKLHPEVHGPYQDTLEFLL 251
Cdd:cd13193      1 ETARRCELYGIRLHPAKDREGVKLNLAVAHMGILVFQGFTKINTFSWAKIRKLSFKRKRFLIKLHPEAYGSYKDTVEFSF 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|..
gi 2462578961  252 GSRDECKNFWKICVEYHTFFRLLDQPKPKA-KAVFFSRGSSF 292
Cdd:cd13193     81 ESRNECKSFWKKCIEHHAFFRCSEVPKPPSpKLRLFSRGSSF 122

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 2462578961  700 LIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSKGVAGTSHFRIRGLLPLQGMLlivldppVEESDNEWSVPHCF 779
Cdd:cd01220      1 LVQPGREFIREGCLQKLSKKGLQQRMFFLFSDVLLYTSRSPTPSLQFKVHGQLPLRGLM-------VEESEPEWGVAHCF 73

                           90       100       110
                   ....*....|....*....|....*....|....
gi 2462578961  780 TIYAAQKTIVVAASTRLEKEKWMLDLNSAIQAAK 813
Cdd:cd01220     74 TIYGGNRALTVAASSEEEKERWLEDLQRAIDAAK 107

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM, ARH/RhoGEF and pleckstrin domain-containing protein 2 (FARP2) and similar proteins; FARP2, also termed FERM domain including RhoGEF (FIR), or Pleckstrin homology (PH) domain-containing family C member 3, is a Dbl-family guanine nucleotide exchange factor (GEF) that activates Rac1 or Cdc42 in response to upstream signals, suggesting roles in regulating processes such as neuronal axon guidance and bone homeostasis. It is also a key molecule involved in the response of neuronal growth cones to class-3 semaphorins. FARP2 contains a FERM domain, a Dbl-homology (DH) domain and two pleckstrin homology (PH) domains. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2462578961   12 QPKCDGQVLLTQVWKRLNLVECDYFGMEFQNTQSYWIWLEPMKPIIRQIRRPKNVVLRLAVKFFPPDP 79
Cdd:cd17190     18 EPKADGQALLSQVFKRLNLVESDYFGLEFQNSQSNWIWLEPMKLIVKQVRRPKNTKLRLAVKFFPPDP 85

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 2462578961   490 IVKEILATERTYLKDLEVITVWFRSAVVKE-DAMPATLMTLLFSNIDPIYEFHRGFLREVEQRLALWEGPskahtkgsHQ 568
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKElKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDS--------VE 72

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961   569 RIGDILLRNMRQLKEFTSYFQRHDEVLTELEKATKRcKKLEAVYKEFELQKVCY-LPLNTFLLKPIQRLLHYRLLLRRLC 647
Cdd:smart00325   73 RIGDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKN-PRFQKFLKEIESSPQCRrLTLESLLLKPVQRLTKYPLLLKELL 151

                           170       180
                    ....*....|....*....|....*...
gi 2462578961   648 GHYSPGHHDYADCHDALKAITEVTTTLQ 675
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 2462578961  490 IVKEILATERTYLKDLEVITVWFRSAVVKEDAMPATLMTLLFSNIDPIYEFHRGFLreVEQRLALWEgpskahtkgSHQR 569
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLKEWI---------SIQR 69

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961  570 IGDILLRNMRQLKEFTSYFQRHDEVLTELEKATKRCKKLEAVYKEFELQKVCY-LPLNTFLLKPIQrllhyrlllrrLCG 648
Cdd:pfam00621   70 IGDIFLKFAPGFKVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRgLDLNSFLIKPVQ-----------RIP 138

                          170       180       190
                   ....*....|....*....|....*....|....*
gi 2462578961  649 HY-----------SPGHHDYADCHDALKAITEVTT 672
Cdd:pfam00621  139 RYplllkellkhtPPDHPDYEDLKKALEAIKEVAK 173

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 2462578961   890 LSGYLLRKFKN-SHGWQKLWVVFTNFCLFFYKTHQDDY---PLASLPLLGYSVSIPREADGIHKDYVFKLQFKS-HVYFF 964
Cdd:smart00233    3 KEGWLYKKSGGgKKSWKKRYFVLFNSTLLYYKSKKDKKsykPKGSIDLSGCTVREAPDPDSSKKPHCFEIKTSDrKTLLL 82

                            90       100
                    ....*....|....*....|
gi 2462578961   965 RAESKYTFERWMEVIQGASS 984
Cdd:smart00233   83 QAESEEEREKWVEALRKAIA 102

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961   707 FIREGCLHKLT---KKGLQQRMFFLFSDMLLYTSKGVAGTShFRIRGLLPLQGMllIVLDPPVEESDNEwsvPHCFTI-Y 782
Cdd:smart00233    1 VIKEGWLYKKSgggKKSWKKRYFVLFNSTLLYYKSKKDKKS-YKPKGSIDLSGC--TVREAPDPDSSKK---PHCFEIkT 74

                            90       100
                    ....*....|....*....|....*...
gi 2462578961   783 AAQKTIVVAASTRLEKEKWMLDLNSAIQ 810
Cdd:smart00233   75 SDRKTLLLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961  708 IREGCLHKLT---KKGLQQRMFFLFSDMLLYTSKGVAGTSHfRIRGLLPLQGmlLIVLDPPVEESDNEwsvPHCFTIYAA 784
Cdd:pfam00169    2 VKEGWLLKKGggkKKSWKKRYFVLFDGSLLYYKDDKSGKSK-EPKGSISLSG--CEVVEVVASDSPKR---KFCFELRTG 75

                           90       100
                   ....*....|....*....|....*....
gi 2462578961  785 Q----KTIVVAASTRLEKEKWMLDLNSAI 809
Cdd:pfam00169   76 ErtgkRTYLLQAESEEERKDWIKAIQSAI 104

FERM domain C-lobe of FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins; 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 FRMD7(FERM domain containing 7). FARP1 and FARP2 are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. 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. These members are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. Other members in this family do not contain the DH domains such as the Human FERM domain containing protein 7 and Caenorhabditis elegans CFRM3, both of which have unknown functions. They contain an N-terminal FERM domain, a PH domain, followed by a FA (FERM adjacent) domain. 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 2462578961  172 EIARKLEMYGIRFHMASDREGTKIQLAVSHMGVLVFQGTTKINTFNWSKVRKLSFKRKRFLIKLHPEVHGPYQDTLEFLL 251
Cdd:cd13193      1 ETARRCELYGIRLHPAKDREGVKLNLAVAHMGILVFQGFTKINTFSWAKIRKLSFKRKRFLIKLHPEAYGSYKDTVEFSF 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|..
gi 2462578961  252 GSRDECKNFWKICVEYHTFFRLLDQPKPKA-KAVFFSRGSSF 292
Cdd:cd13193     81 ESRNECKSFWKKCIEHHAFFRCSEVPKPPSpKLRLFSRGSSF 122

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 2462578961  700 LIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSKGVAGTSHFRIRGLLPLQGMLlivldppVEESDNEWSVPHCF 779
Cdd:cd01220      1 LVQPGREFIREGCLQKLSKKGLQQRMFFLFSDVLLYTSRSPTPSLQFKVHGQLPLRGLM-------VEESEPEWGVAHCF 73

                           90       100       110
                   ....*....|....*....|....*....|....
gi 2462578961  780 TIYAAQKTIVVAASTRLEKEKWMLDLNSAIQAAK 813
Cdd:cd01220     74 TIYGGNRALTVAASSEEEKERWLEDLQRAIDAAK 107

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM, ARH/RhoGEF and pleckstrin domain-containing protein 2 (FARP2) and similar proteins; FARP2, also termed FERM domain including RhoGEF (FIR), or Pleckstrin homology (PH) domain-containing family C member 3, is a Dbl-family guanine nucleotide exchange factor (GEF) that activates Rac1 or Cdc42 in response to upstream signals, suggesting roles in regulating processes such as neuronal axon guidance and bone homeostasis. It is also a key molecule involved in the response of neuronal growth cones to class-3 semaphorins. FARP2 contains a FERM domain, a Dbl-homology (DH) domain and two pleckstrin homology (PH) domains. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2462578961   12 QPKCDGQVLLTQVWKRLNLVECDYFGMEFQNTQSYWIWLEPMKPIIRQIRRPKNVVLRLAVKFFPPDP 79
Cdd:cd17190     18 EPKADGQALLSQVFKRLNLVESDYFGLEFQNSQSNWIWLEPMKLIVKQVRRPKNTKLRLAVKFFPPDP 85

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 2462578961   490 IVKEILATERTYLKDLEVITVWFRSAVVKE-DAMPATLMTLLFSNIDPIYEFHRGFLREVEQRLALWEGPskahtkgsHQ 568
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKElKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDS--------VE 72

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961   569 RIGDILLRNMRQLKEFTSYFQRHDEVLTELEKATKRcKKLEAVYKEFELQKVCY-LPLNTFLLKPIQRLLHYRLLLRRLC 647
Cdd:smart00325   73 RIGDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKN-PRFQKFLKEIESSPQCRrLTLESLLLKPVQRLTKYPLLLKELL 151

                           170       180
                    ....*....|....*....|....*...
gi 2462578961   648 GHYSPGHHDYADCHDALKAITEVTTTLQ 675
Cdd:smart00325  152 KHTPEDHEDREDLKKALKAIKELANQVN 179

FERM C-terminal PH-like domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961  189 DREGTKIQLAVSHMGVLVFQGTTKI-NTFNWSKVRKLSFKRKRFLIKLHpevHGPYQDTLEFLLGSRDECKNFWKICVEY 267
Cdd:pfam09380    1 DKEGTDLWLGVSAKGILVYEDNNKIlNLFPWREIRKISFKRKKFLIKLR---DKSSEETLGFYTESSRACKYLWKLCVEQ 77

                   ....*.
gi 2462578961  268 HTFFRL 273
Cdd:pfam09380   78 HTFFRL 83

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 2462578961  490 IVKEILATERTYLKDLEVITVWFRSAVVKEDAMPATLMTLLFSNIDPIYEFHRGFLreVEQRLALWEgpskahtkgSHQR 569
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLKEWI---------SIQR 69

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961  570 IGDILLRNMRQLKEFTSYFQRHDEVLTELEKATKRCKKLEAVYKEFELQKVCY-LPLNTFLLKPIQrllhyrlllrrLCG 648
Cdd:pfam00621   70 IGDIFLKFAPGFKVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRgLDLNSFLIKPVQ-----------RIP 138

                          170       180       190
                   ....*....|....*....|....*....|....*
gi 2462578961  649 HY-----------SPGHHDYADCHDALKAITEVTT 672
Cdd:pfam00621  139 RYplllkellkhtPPDHPDYEDLKKALEAIKEVAK 173

FERM central domain; This domain is the central structural domain of the FERM domain.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462578961   77 PDPGQLQEEYTRYLFALQLKRDLLEERLTCADTTAALLTSHLLQSEIGDY-DETLDREHLKVNEYLP-------GQQHCL 148
Cdd:pfam00373    1 DLELLLQDEVTRHLLYLQAKDDILEGRLPCSEEEALLLAALQLQAEFGDYqPSSHTSEYLSLESFLPkqllrkmKSKELE 80

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 2462578961  149 EKILEFHQKHVGQTPAESDFQVLEIARKLEMYGIRFH 185
Cdd:pfam00373   81 KRVLEAHKNLRGLSAEEAKLKYLQIAQSLPTYGVEFF 117

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 2462578961  694 LVGIENLIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSKgVAGTSHFRIRGLLPLQGMLLIvldPPVEEsdnew 773
Cdd:cd13389      1 LLGQYNIVKPGRKLIKEGELMKVSRKEMQPRYFFLFNDCLLYTTP-VQSSGMLKLNNELPLSGMKVK---LPEDE----- 71

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 2462578961  774 SVPHCFTIYAAQKTIVVAASTRLEKEKWMLDLNSAIQAAKS 814
Cdd:cd13389     72 EYSNEFQIISTKRSFTLIASSEEERDEWVKALSRAIEEHTK 112

FERM N-terminal domain; This domain is the N-terminal ubiquitin-like structural domain of the FERM domain.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2462578961   10 LCQPKCDGQVLLTQVWKRLNLVECDYFGMEFQNTQSYWIWLEPMKPIIRQIR 61
Cdd:pfam09379   12 DVQPKATGQVLLDQVCNHLNLKEKDYFGLQFLDDNGEHRWLDLSKRLSKQAP 63

FERM domain C-lobe of Novel band 4.1-like protein 4 and 5 (NBL4 and 5); NBL4 (also called Erythrocyte protein band 4.1-like 4; Epb4 1l4) plays a role the beta-catenin/Tcf signaling pathway and is thought to be involved in establishing the cell polarity or proliferation. NBL4 may be also involved in adhesion, in cell motility and/or in cell-to-cell communication. No role for NBL5 has been proposed to date. Both NBL4 and NBL5 contain a N-terminal FERM domain which 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 is a member of the PH superfamily. 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 2462578961  181 GIRFHMASDREGTKIQLAVSHMGVLVFQGTTKINTFNWSKVRKLSFKRKRFLIKLHPEVHGPYQDTLEFLLGSRDECKNF 260
Cdd:cd13186      1 GVDLHPVKGEDGNEYFLGLTPTGILVFENKTKIGLFFWPRITKLDFKGKKLKLVVKEKDDQEQEHTFVFRLPNKKACKHL 80

                           90
                   ....*....|..
gi 2462578961  261 WKICVEYHTFFR 272
Cdd:cd13186     81 WKCAVEHHAFFR 92

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in FERM domain-containing protein 7 (FRMD7); FRMD7 plays an important role in neuronal development and is involved in the regulation of F-actin, neurofilament, and microtubule dynamics. It interacts with the Rho GTPase regulator, RhoGDIalpha, and activates the Rho subfamily member Rac1, which regulates reorganization of actin filaments and controls neuronal outgrowth. Mutations in the FRMD7 gene are responsible for the X-linked idiopathic congenital nystagmus (ICN), a disease which affects ocular motor control. FRMD7 contains a FERM domain, and a pleckstrin homology (PH) domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462578961   14 KCDGQVLLTQVWKRLNLVECDYFGMEFQNTQSYWIWLEPMKPIIRQIRRPKNVVLRLAVKFFPPDP 79
Cdd:cd17188     21 KSTGKDLFNMSCSHLNLVEKEYFGLEFRNHAGNNVWLELLKPITKQIKNPKELIFKFTVKFFPVDP 86

FERM domain C-lobe of FERM domain-containing protein 3 and 5 (FRMD3 and 5); FRMD3 (also called Band 4.1-like protein 4O/4.1O though it is not a true member of that family) is a novel putative tumor suppressor gene that is implicated in the origin and progression of lung cancer. In humans there are 5 isoforms that are produced by alternative splicing. Less is known about FRMD5, though there are 2 isoforms of the human protein are produced by alternative splicing. Both FRMD3 and FRMD5 contain a N-terminal FERM domain, followed by a FERM adjacent (FA) domain, and 4.1 protein C-terminal domain (CTD). 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 2462578961  164 AESDFqvLEIARKLEMYGIRFHMASDREGTKIQLAVSHMGVLVFQGTTKINTFNWSKVRKLSFKRKRFLIKLHpeVHGPY 243
Cdd:cd13192      1 AEDNF--LRKAATLETYGVDPHPVKDHRGNQLYLGFTHTGIVTFQGGKRVHHFRWNDITKFNYEGKMFILHVM--QKEEK 76

                           90       100
                   ....*....|....*....|....*....
gi 2462578961  244 QDTLEFLLGSRDECKNFWKICVEYHTFFR 272
Cdd:cd13192     77 KHTLGFKCPTPAACKHLWKCAVEQQAFYT 105

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 2462578961   890 LSGYLLRKFKN-SHGWQKLWVVFTNFCLFFYKTHQDDY---PLASLPLLGYSVSIPREADGIHKDYVFKLQFKS-HVYFF 964
Cdd:smart00233    3 KEGWLYKKSGGgKKSWKKRYFVLFNSTLLYYKSKKDKKsykPKGSIDLSGCTVREAPDPDSSKKPHCFEIKTSDrKTLLL 82

                            90       100
                    ....*....|....*....|
gi 2462578961   965 RAESKYTFERWMEVIQGASS 984
Cdd:smart00233   83 QAESEEEREKWVEALRKAIA 102

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 2462578961  284 VFFSRGSSFRYSGRTQKQLVDYFKDSGMKRIPYERRHSKTHTS 326
Cdd:pfam08736    1 KFFSLGSKFRYSGRTQKQTVEDSSEILRPQPEFERSPSKRYPS 43

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 2462578961  681 LENLQKLTELQRDLVG--IENLIAPGREFIREGCLHKLTKKGLQQRMFFLFSDMLLYTSKGVAGTSHFRIRGLLPLQGML 758
Cdd:cd01224      1 MENLEKLAAWQSTVEGweGEDLSDRSSELIHSGELTKISAGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDNME 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 2462578961  759 LIVLdPPVEESDNEWSVPHCFTIY--AAQKTIVVAASTRLEKEKWM 802
Cdd:cd01224     81 IEDL-PDGKDDESGVTVKNAWKIYnaSKNKWYVLCAKSAEEKQRWL 125