Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309 367 LIKEGSIQKLSAKNGTTQDRHLFLFNNVMLYCVPKLRLMGQKLSVREKMDISDLQVQDIVKPNAACTFIITGRKRSLELQ 446
Cdd:cd13387   1 LIKEGHIQKLSAKNGTAQDRYLYLFNSMVLYCVPKLRLMGQKFSVREKIDIAGMQVQEIVKQNVPHTFTITGKKRSLELQ 80

                        90       100
                ....*....|....*....|....*...
gi 85719309 447 TRTEEEKKEWIQVIQATVEKHKQKSETF 474
Cdd:cd13387  81 ARTEEEKKEWIQVIQATIEKHKQNSETF 108

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 85719309 606 PSVDPRPSLLCGTLNLSDDGTTWNEVWAAIPESDPQVLDLLAGSQAGRLLYSIPLSGCNITMPDPEEGLEAGCAWKLHQG 685
Cdd:cd13236   1 ASAVPENSLLCGFLQYSEKGKTWQKVWCVIPRTEPLVLYLYGAPQDVRAQRTIPLPGCEVTVPPPEERLDGRHVFKLSQS 80

                        90       100
                ....*....|....*....|....*
gi 85719309 686 SQTWWLSAPSTKLQQCWLKALGTAV 710
Cdd:cd13236  81 KQSHYFSAESEELQQRWLEALSRAA 105

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309 367 LIKEGSIQKLSAKNGTTQDRHLFLFNNVMLYCVPKLRLMGQKLSVREKMDISDLQVQDIVKPNAACTFIITGRKRSLELQ 446
Cdd:cd13387   1 LIKEGHIQKLSAKNGTAQDRYLYLFNSMVLYCVPKLRLMGQKFSVREKIDIAGMQVQEIVKQNVPHTFTITGKKRSLELQ 80

                        90       100
                ....*....|....*....|....*...
gi 85719309 447 TRTEEEKKEWIQVIQATVEKHKQKSETF 474
Cdd:cd13387  81 ARTEEEKKEWIQVIQATIEKHKQNSETF 108

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 85719309 156 HIAQELLHTEEAYVKRLHLLDQVFCTKLTEAGIPL---EVTTgIFSNISSIYRFHGQFLLpELQKRITEEWDTNPRLGDI 232
Cdd:cd00160   3 EVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLspeEVEL-LFGNIEEIYEFHRIFLK-SLEERVEEWDKSGPRIGDV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309 233 LQKLAPFLKMYGEYVKNFDRAMGLVSTWTQRSPQFKDVIHtiQKQEVCGNLTLQHHMLEPVQRVPRYELLLKDYLKRLPR 312
Cdd:cd00160  81 FLKLAPFFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLE--KAESECGRLKLESLLLKPVQRLTKYPLLLKELLKHTPD 158

                       170       180
                ....*....|....*....|...
gi 85719309 313 DAPDRKDAERSLELISTAADHSN 335
Cdd:cd00160 159 GHEDREDLKKALEAIKEVASQVN 181

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 85719309 606 PSVDPRPSLLCGTLNLSDDGTTWNEVWAAIPESDPQVLDLLAGSQAGRLLYSIPLSGCNITMPDPEEGLEAGCAWKLHQG 685
Cdd:cd13236   1 ASAVPENSLLCGFLQYSEKGKTWQKVWCVIPRTEPLVLYLYGAPQDVRAQRTIPLPGCEVTVPPPEERLDGRHVFKLSQS 80

                        90       100
                ....*....|....*....|....*
gi 85719309 686 SQTWWLSAPSTKLQQCWLKALGTAV 710
Cdd:cd13236  81 KQSHYFSAESEELQQRWLEALSRAA 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 85719309    367 LIKEGSIQKLSA-KNGTTQDRHLFLFNNVMLYCvpKLRLMGQKLSVREKMDISDLQVQDIVKPNAA---CTF-IITGRKR 441
Cdd:smart00233   1 VIKEGWLYKKSGgGKKSWKKRYFVLFNSTLLYY--KSKKDKKSYKPKGSIDLSGCTVREAPDPDSSkkpHCFeIKTSDRK 78

                           90       100
                   ....*....|....*....|...
gi 85719309    442 SLELQTRTEEEKKEWIQVIQATV 464
Cdd:smart00233  79 TLLLQAESEEEREKWVEALRKAI 101

Protein present in Fab1, YOTB, Vac1, and EEA1; The FYVE zinc finger is named after four proteins where it was first found: Fab1, YOTB/ZK632.12, Vac1, and EEA1. The FYVE finger has been shown to bind two Zn2+ ions. The FYVE finger has eight potential zinc coordinating cysteine positions. The FYVE finger is structurally related to the PHD finger and the RING finger. Many members of this family also include two histidines in a motif R+HHC+XCG, where + represents a charged residue and X any residue. The FYVE finger functions in the membrane recruitment of cytosolic proteins by binding to phosphatidylinositol 3-phosphate (PI3P), which is prominent on endosomes. The R+HHC+XCG motif is critical for PI3P binding.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 85719309    527 RDKEKPGCKSCGETFNsITKRRYRCKLCGEVICRKCSEFKA-----ENSKQSRVCRECF 580
Cdd:smart00064   6 PDEEVSNCMGCGKEFN-LTKRRHHCRNCGRIFCSKCSSKKAplpklGIERPVRVCDDCY 63

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309  160 ELLHTEEAYVKRLHLLDQVFCTKLTEAG-IP----LEVTTGIFSNISSIYRFHGQFLlPELQKRITEEwDTNPRLGDILQ 234
Cdd:COG5422  491 EVIYTERDFVKDLEYLRDTWIKPLEESNiIPenarRNFIKHVFANINEIYAVNSKLL-KALTNRQCLS-PIVNGIADIFL 568

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309  235 KLAPFLKMYGEYVKNfdRAMGLVSTWTQRS--PQFKDVIHTIQKQEVCGNLTLQHHMLEPVQRVPRYELLLKDYLKRLPR 312
Cdd:COG5422  569 DYVPKFEPFIKYGAS--QPYAKYEFEREKSvnPNFARFDHEVERLDESRKLELDGYLTKPTTRLARYPLLLEEVLKFTDP 646

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309  313 DAPDRKDAERSLELISTAADHSNAAIRKMEKMHKLLEVYEQLGGEEDIVN-----PANELIKEG--SIQKLSAKNGTTQ- 384
Cdd:COG5422  647 DNPDTEDIPKVIDMLREFLSRLNFESGKAENRGDLFHLNQQLLFKPEYVNlglndEYRKIIFKGvlKRKAKSKTDGSLRg 726

                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309  385 DRHLFLFNNVMLYCVPK--LRLMGQKLSVR----EKMDIS----DLQVQDIVKPNAACTFI------------------I 436
Cdd:COG5422  727 DIQFFLLDNMLLFCKAKavNKWRQHKVFQRpiplELLFISpdedSPDRAEYLKPAPSADVLdpayntkppknaygfelyG 806

                        330       340       350       360       370       380       390
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 85719309  437 TGRKRSLELQTRTEEEKKEWIQVIQATVEKHKQKSETFRAFGGACsqdeeptlspdQPVMSTSSVEPAGVADSN 510
Cdd:COG5422  807 NGQRYQITLYAETHAGRDTWLEHIKNQQDILRTRTLWFTSFPICD-----------QFFSTTNKVNPVPLYDSG 869

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309 367 LIKEGSIQKLSAKNGTTQDRHLFLFNNVMLYCVPKLRLMGQKLSVREKMDISDLQVQDIVKPNAACTFIITGRKRSLELQ 446
Cdd:cd13387   1 LIKEGHIQKLSAKNGTAQDRYLYLFNSMVLYCVPKLRLMGQKFSVREKIDIAGMQVQEIVKQNVPHTFTITGKKRSLELQ 80

                        90       100
                ....*....|....*....|....*...
gi 85719309 447 TRTEEEKKEWIQVIQATVEKHKQKSETF 474
Cdd:cd13387  81 ARTEEEKKEWIQVIQATIEKHKQNSETF 108

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 85719309 156 HIAQELLHTEEAYVKRLHLLDQVFCTKLTEAGIPL---EVTTgIFSNISSIYRFHGQFLLpELQKRITEEWDTNPRLGDI 232
Cdd:cd00160   3 EVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLspeEVEL-LFGNIEEIYEFHRIFLK-SLEERVEEWDKSGPRIGDV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309 233 LQKLAPFLKMYGEYVKNFDRAMGLVSTWTQRSPQFKDVIHtiQKQEVCGNLTLQHHMLEPVQRVPRYELLLKDYLKRLPR 312
Cdd:cd00160  81 FLKLAPFFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLE--KAESECGRLKLESLLLKPVQRLTKYPLLLKELLKHTPD 158

                       170       180
                ....*....|....*....|...
gi 85719309 313 DAPDRKDAERSLELISTAADHSN 335
Cdd:cd00160 159 GHEDREDLKKALEAIKEVASQVN 181

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 85719309 606 PSVDPRPSLLCGTLNLSDDGTTWNEVWAAIPESDPQVLDLLAGSQAGRLLYSIPLSGCNITMPDPEEGLEAGCAWKLHQG 685
Cdd:cd13236   1 ASAVPENSLLCGFLQYSEKGKTWQKVWCVIPRTEPLVLYLYGAPQDVRAQRTIPLPGCEVTVPPPEERLDGRHVFKLSQS 80

                        90       100
                ....*....|....*....|....*
gi 85719309 686 SQTWWLSAPSTKLQQCWLKALGTAV 710
Cdd:cd13236  81 KQSHYFSAESEELQQRWLEALSRAA 105

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia family 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). 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 85719309 369 KEGSIQKLSAKNGTTQDRHLFLFNNVMLYCVPKLRLMGQKLSVREKMDISDLQVQDIVKPNAACTFIITGRKRSLELQTR 448
Cdd:cd13328   1 KEGQILKLSAKNGTPQPRYLFLFNDMLLYCVPKLSLVGQKFSVRNRLDVAGMKVREPVNENYPHTFKISGKERSLELQAS 80

                        90
                ....*....|..
gi 85719309 449 TEEEKKEWIQVI 460
Cdd:cd13328  81 SAEEKDEWIQAI 92

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 2, 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. 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). 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 85719309 367 LIKEGSIQKLSAKNGTTQDRHLFLFNNVMLYCVPKLRLMGQKLSVREKMDISDLQVQDIVKPNAACTFIITGRKRSLELQ 446
Cdd:cd13386   1 LLKEGPVLKISFRNNNPKERYLFLFNNMLLYCVPKVIQVGAKFQVHMRIDVDGMKVRELNDAEFPHSFLVSGKQRTLELQ 80

                        90       100
                ....*....|....*....|....*...
gi 85719309 447 TRTEEEKKEWIQVIQATVEKHKQKSETF 474
Cdd:cd13386  81 ARSQEEMEAWIQAFQEAIDQNEKRTETF 108

FYVE-like domain found in FYVE, RhoGEF and PH domain-containing protein 3 (FGD3) and similar proteins; FGD3, also termed zinc finger FYVE domain-containing protein 5, is a putative Cdc42-specific guanine nucleotide exchange factor (GEF) that undergoes the ubiquitin ligase SCFFWD1/beta-TrCP-mediated proteasomal degradation. It is a homologue of FGD1 and contains a DBL homology (DH) domain and pleckstrin homology (PH) domain in the middle region, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. Due to this difference, FGD3 may play different roles from that of FGD1 to regulate cell morphology or motility. The FYVE domain of FGD3 resembles a FYVE-like domain that is different from the canonical FYVE domains, since it lacks one of the three conserved signature motifs (the WxxD motif) that are involved in phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding and exhibits altered lipid binding specificities.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 85719309 527 RDKEKPGCKSCGETFNSITKRRYRCKLCGEVICRKCSEFKAENSKQSRVCRECF 580
Cdd:cd15740   1 REKEKQTCKGCNESFNSITKRRHHCKQCGAVICGKCSEFKDLASRHNRVCRDCF 54

FYVE domain found in FYVE, RhoGEF and PH domain-containing protein facio-genital dysplasia FGD1, FGD2, FGD4; This family represents a group of Rho GTPase cell division cycle 42 (Cdc42)-specific guanine nucleotide exchange factors (GEFs), including FYVE, RhoGEF and PH domain-containing protein FGD1, FGD2 and FGD4. FGD1, also termed faciogenital dysplasia 1 protein, or Rho/Rac guanine nucleotide exchange factor FGD1 (Rho/Rac GEF), or zinc finger FYVE domain-containing protein 3, is a central regulator of extracellular matrix remodeling and belongs to the DBL family of GEFs that regulate the activation of the Rho GTPases. FGD1 is encoded by gene FGD1. Disabling mutations in the FGD1 gene cause the human X-linked developmental disorder faciogenital dysplasia (FGDY, also known as Aarskog-Scott syndrome). FGD2, also termed zinc finger FYVE domain-containing protein 4, is expressed in antigen-presenting cells, including B lymphocytes, macrophages, and dendritic cells. It localizes to early endosomes and active membrane ruffles. It plays a role in leukocyte signaling and vesicle trafficking in cells specialized to present antigen in the immune system. FGD4, also termed actin filament-binding protein frabin, or FGD1-related F-actin-binding protein, or zinc finger FYVE domain-containing protein 6, functions as an F-actin-binding (FAB) protein showing significant homology to FGD1. It induces the formation of filopodia through the activation of Cdc42 in fibroblasts. Those FGD proteins possess a similar domain organization that contains a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a FYVE domain, and another PH domain in the C-terminus. However, each FGD has a unique N-terminal region that may directly or indirectly interact with F-actin. FGD1 and FGD4 have an N-terminal proline-rich domain (PRD) and an N-terminal F-actin binding (FAB) domain, respectively. This model corresponds to the FYVE domain, which has been found in many proteins involved in membrane trafficking and phosphoinositide metabolism, and has been defined by three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCR patch, and a C-terminal RVC motif, which form a compact phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding site. FGD1 possesses a FYVE-like domain that lack the N-terminal WxxD motif. Moreover, FGD2 is the only known RhoGEF family member shown to have a functional FYVE domain and endosomal binding activity.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 85719309 527 RDKEKPGCKSCGETFNSITKRRYRCKLCGEVICRKCSEFKAE----NSKQSRVCRECF 580
Cdd:cd15741   5 RDNEVTMCMRCKEPFNALTRRRHHCRACGYVVCWKCSDYKATleydGNKLNRVCKHCY 62

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309   367 LIKEGSIQKLSAKNGTT-QDRHLFLFNNVMLYCvpKLRLMGQKLSVREKMDISDLQVQDIV---KPNAACTFIIT----G 438
Cdd:pfam00169   1 VVKEGWLLKKGGGKKKSwKKRYFVLFDGSLLYY--KDDKSGKSKEPKGSISLSGCEVVEVVasdSPKRKFCFELRtgerT 78

                          90       100
                  ....*....|....*....|....*..
gi 85719309   439 RKRSLELQTRTEEEKKEWIQVIQATVE 465
Cdd:pfam00169  79 GKRTYLLQAESEEERKDWIKAIQSAIR 105

FYVE zinc finger; The FYVE zinc finger is named after four proteins that it has been found in: Fab1, YOTB/ZK632.12, Vac1, and EEA1. The FYVE finger has been shown to bind two Zn++ ions. The FYVE finger has eight potential zinc coordinating cysteine positions. Many members of this family also include two histidines in a motif R+HHC+XCG, where + represents a charged residue and X any residue. We have included members which do not conserve these histidine residues but are clearly related.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 85719309   528 DKEKPGCKSCGETFNsITKRRYRCKLCGEVICRKCSEFKAEN------SKQSRVCRECF 580
Cdd:pfam01363   6 DSSATVCMICSKPFT-FFRRRHHCRNCGRVFCSACSSKKISLlpelgsNKPVRVCDACY 63

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309  160 ELLHTEEAYVKRLHLLDQVFCTKLTEAG-IP----LEVTTGIFSNISSIYRFHGQFLlPELQKRITEEwDTNPRLGDILQ 234
Cdd:COG5422  491 EVIYTERDFVKDLEYLRDTWIKPLEESNiIPenarRNFIKHVFANINEIYAVNSKLL-KALTNRQCLS-PIVNGIADIFL 568

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309  235 KLAPFLKMYGEYVKNfdRAMGLVSTWTQRS--PQFKDVIHTIQKQEVCGNLTLQHHMLEPVQRVPRYELLLKDYLKRLPR 312
Cdd:COG5422  569 DYVPKFEPFIKYGAS--QPYAKYEFEREKSvnPNFARFDHEVERLDESRKLELDGYLTKPTTRLARYPLLLEEVLKFTDP 646

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309  313 DAPDRKDAERSLELISTAADHSNAAIRKMEKMHKLLEVYEQLGGEEDIVN-----PANELIKEG--SIQKLSAKNGTTQ- 384
Cdd:COG5422  647 DNPDTEDIPKVIDMLREFLSRLNFESGKAENRGDLFHLNQQLLFKPEYVNlglndEYRKIIFKGvlKRKAKSKTDGSLRg 726

                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85719309  385 DRHLFLFNNVMLYCVPK--LRLMGQKLSVR----EKMDIS----DLQVQDIVKPNAACTFI------------------I 436
Cdd:COG5422  727 DIQFFLLDNMLLFCKAKavNKWRQHKVFQRpiplELLFISpdedSPDRAEYLKPAPSADVLdpayntkppknaygfelyG 806

                        330       340       350       360       370       380       390
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 85719309  437 TGRKRSLELQTRTEEEKKEWIQVIQATVEKHKQKSETFRAFGGACsqdeeptlspdQPVMSTSSVEPAGVADSN 510
Cdd:COG5422  807 NGQRYQITLYAETHAGRDTWLEHIKNQQDILRTRTLWFTSFPICD-----------QFFSTTNKVNPVPLYDSG 869

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 85719309 354 LGGEEDIVNPANELIKEGSIQKLSAKngTTQDRHLFLFNNVMLYCVPklrLMGQKLSVREKMDISDLQVQDIVKPNAACT 433
Cdd:cd15793   1 LNGHHEIVQPGRVFLKEGTLMKLSRK--VMQPRMFFLFNDALLYTTP---VQSGMYKLNNMLSLAGMKVSKPSQEAYQNE 75

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 85719309 434 FIITGRKRSLELQTRTEEEKKEWIQVIQATVEKHKQKSETF 474
Cdd:cd15793  76 LNIESVERSFILSASSATERDEWLEAISRAIEEYAKKKITF 116

FYVE domain like superfamily; FYVE domain is a 60-80 residue double zinc finger motif-containing module named after the four proteins, Fab1, YOTB, Vac1, and EEA1. The canonical FYVE domains are distinguished from other zinc fingers by three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif, which form a compact phosphatidylinositol 3-phosphate (PtdIns3P, also termed PI3P)-binding site. They are found in many membrane trafficking regulators, including EEA1, Hrs, Vac1p, Vps27p, and FENS-1, which locate to early endosomes, specifically bind PtdIns3P, and play important roles in vesicular traffic and in signal transduction. Some proteins, such as rabphilin-3A and alpha-Rab3-interacting molecules (RIMs), are also involved in membrane trafficking and bind to members of the Rab subfamily of GTP hydrolases. However, they contain FYVE-related domains that are structurally similar to the canonical FYVE domains but lack the three signature sequences. At this point, they may not bind to phosphoinositides. In addition, this superfamily also contains the third group of proteins, caspase-associated ring proteins CARP1 and CARP2. They do not localize to membranes in the cell and are involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8 and caspase 10, which are distinguished from other FYVE-type proteins. Moreover, these proteins have an altered sequence in the basic ligand binding patch and lack the WxxD motif that is conserved only in phosphoinositide binding FYVE domains. Thus they constitute a family of unique FYVE-type domains called FYVE-like domains. The FYVE domain is structurally similar to the RING domain and the PHD finger. This superfamily also includes ADDz zinc finger domain, which is a PHD-like zinc finger motif that contains two parts, a C2-C2 and a PHD-like zinc finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 85719309 534 CKSCGETFnSITKRRYRCKLCGEVICRKCSEFKA-----ENSKQSRVCRECF 580
Cdd:cd00065   2 CMLCGKKF-SLFRRRHHCRRCGRVFCSKCSSKKLplpsfGSGKPVRVCDSCY 52

FYVE domain found in WD40 repeat and FYVE domain-containing protein 3 (WDFY3) and similar proteins; WDFY3, also termed autophagy-linked FYVE protein (Alfy), is a ubiquitously expressed phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein required for selective macroautophagic degradation of aggregated proteins. It regulates the protein degradation through the direct interaction with the autophagy protein Atg5. Moreover, WDFY3 acts as a scaffold that bridges its cargo to the macroautophagic machinery via the creation of a greater complex with Atg12, Atg16L, and LC3. It also functionally associates with sequestosome-1/p62 (SQSTM1) in osteoclasts. WDFY3 shuttles between the nucleus and cytoplasm. It predominantly localizes to the nucleus and nuclear membrane under basal conditions, but is recruited to cytoplasmic ubiquitin-positive protein aggregates under stress conditions. WDFY3 contains a PH-BEACH domain assemblage, five WD40 repeats and a PtdIns3P-binding FYVE domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 85719309 527 RDKEKPGCKSCGETFnSITKRRYRCKLCGEVICRKCSEFKAE-----NSKQSRVCRECF 580
Cdd:cd15719   5 KDEGGDSCTGCSVRF-SLTERRHHCRNCGQLFCSKCSRFESEirrlrISRPVRVCQACY 62

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 85719309 341 MEKMHKLLEVYEQLGG--EEDIVNPANELIKEGSIQKLSAknGTTQDRHLFLFNNVMLYCVPKLRLmGQKLSVREKMDIS 418
Cdd:cd01224   1 MENLEKLAAWQSTVEGweGEDLSDRSSELIHSGELTKISA--GRAQERTFFLFDHQLVYCKKDLLR-RKNYIYKGRIDTD 77

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 85719309 419 DLQVQDI-----------VKpNAactFIITGRKRS--LELQTRTEEEKKEWIQVIQATVEKHKQ 469
Cdd:cd01224  78 NMEIEDLpdgkddesgvtVK-NA---WKIYNASKNkwYVLCAKSAEEKQRWLEAFAEEREKVEK 137

Son of Sevenless (SOS) Pleckstrin homology (PH) domain; SOS is a Ras guanine nucleotide exchange factor. SOS is thought to transmit signals from activated receptor tyrosine kinases to the Ras signaling pathway. SOS contains a histone domain, Dbl-homology (DH), a PH domain, Rem domain, Cdc25 domain, and a Grb2 binding domain. The SOS PH domain binds to phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidic acid (PA). SOS is dependent on Ras binding to the allosteric site via its histone domain for both a lower level of activity (Ras GDP) and maximal activity (Ras GTP). The DH domain blocks the allosteric Ras binding site in SOS. The PH domain is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS. The C-terminal proline-rich domain of SOS binds to the adapter protein Grb2 which localizes the Sos protein to the plasma membrane and diminishes the negative effect of the C-terminal domain on the guanine nucleotide exchange activity of the CDC25-homology domain of SOS. 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 85719309 365 NELIKEGSIQKLSAKNGTTqDRHLFLFNNVMLYC------------VPKLRLMGqKLSVReKMDISDLQVQDIVKpNAac 432
Cdd:cd01261   4 NEFIMEGTLGKVGSGKRKT-ERHAFLFDGLLLLCksnrrrtstggpKPEYRLKE-KFFIR-KVEINDLEDTEELK-NA-- 77

                        90       100
                ....*....|....*....|....*
gi 85719309 433 tF-IITGRKRSLELQTRTEEEKKEW 456
Cdd:cd01261  78 -FeIVPRDQPSVILFAKSAEEKNNW 101

FYVE domain found in FYVE, RhoGEF and PH domain-containing protein 6 (FGD6) and similar proteins; FGD6, also termed zinc finger FYVE domain-containing protein 24 is a putative Cdc42-specific guanine nucleotide exchange factor (GEF) whose biological function remains unclear. It is a homologue of FGD1 and contains a DBL homology (DH) domain and pleckstrin homology (PH) domain in the middle region, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. Moreover, the FYVE domain of FGD6 is a canonical FYVE domain, which has been found in many proteins involved in membrane trafficking and phosphoinositide metabolism, and has been defined by three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCR patch, and a C-terminal RVC motif, which form a compact phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding site.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 85719309 534 CKSCGETFnSITKRRYRCKLCGEVICRKCSEFKAE----NSKQSRVCRECF 580
Cdd:cd15743  12 CMICTSEF-TVTWRRHHCRACGKVVCGSCSSNKAPleylKNKSARVCDECF 61

FYVE domain found in early endosome antigen 1 (EEA1) and similar proteins; EEA1, also termed endosome-associated protein p162, or zinc finger FYVE domain-containing protein 2, is an essential component of the endosomal fusion machinery and required for the fusion and maturation of early endosomes in endocytosis. It forms a parallel coiled-coil homodimer in cells. EEA1 serves as the p97 ATPase substrate and the p97 ATPase may regulate the size of early endosomes by governing the oligomeric state of EEA1. It can interact with the GTP-bound form of Rab22a and be involved in endosomal membrane trafficking. EEA1 also functions as an obligate scaffold for angiotensin II-induced Akt activation in early endosomes. It can be phosphorylated by p38 mitogen-activated protein kinase (MAPK) and further regulate mu opioid receptor endocytosis. EEA1 consists of an N-terminal C2H2 Zn2+ finger, four long heptad repeats, and a C-terminal region containing a calmodulin binding (IQ) motif, a Rab5 interaction site, and a FYVE domain. This model corresponds to the FYVE domain that is responsible for binding phosphatidyl inositol-3-phosphate (PtdIns3P or PI3P) on the membrane.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 85719309 528 DKEKPGCKSCGETFnSITKRRYRCKLCGEVICRKCSEFKAE--NSKQS-RVCRECFLE 582
Cdd:cd15730   6 DEEVQNCMACGKGF-SVTVRKHHCRQCGNIFCNECSSKTATtpSSKKPvRVCDACFDD 62

FYVE domain found in ankyrin repeat and FYVE domain-containing protein 1 (ANFY1) and similar proteins; ANFY1, also termed ankyrin repeats hooked to a zinc finger motif (Ankhzn), is a novel cytoplasmic protein that belongs to a new group of double zinc finger proteins involved in vesicle or protein transport. It is ubiquitously expressed in a spatiotemporal-specific manner and is located on endosomes. ANFY1 contains an N-terminal coiled-coil region and a BTB/POZ domain, ankyrin repeats in the middle, and a C-terminal FYVE domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 85719309 534 CKSCGETFnSITKRRYRCKLCGEVICRKCSEF-----KAENSKQSRVCRECF 580
Cdd:cd15728  10 CYECGVKF-GITTRKHHCRHCGRLLCSKCSTKevpiiKFDLNKPVRVCDVCF 60

FYVE domain found in Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and similar proteins; scVps27p, also termed Golgi retention defective protein 11, is the putative yeast counterpart of the mammalian protein Hrs and is involved in endosome maturation. It is a mono-ubiquitin-binding protein that interacts with ubiquitinated cargoes, such as Hse1p, and is required for protein sorting into the multivesicular body. Vps27p forms a complex with Hse1p. The complex binds ubiquitin and mediates endosomal protein sorting. At the endosome, Vps27p and a trimeric protein complex, ESCRT-1, bind ubiquitin and are important for multivesicular body (MVB) sorting. Vps27p contains an N-terminal VHS (Vps27/Hrs/STAM) domain, a FYVE domain that binds PtdIns3P, followed by two ubiquitin-interacting motifs (UIMs), and a C-terminal clathrin-binding motif.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 85719309 529 KEKPGCKSCGETFNSiTKRRYRCKLCGEVICRKCSEFK------AENSKQSRVCRECF 580
Cdd:cd15760   3 KPDSRCDVCRKKFGL-FKRRHHCRNCGDSFCSEHSSRRiplphlGPLGVPQRVCDRCF 59

FYVE domain found in zinc finger FYVE domain-containing protein 21 (ZF21) and similar proteins; ZF21 is phosphoinositide-binding protein that functions as a regulator of focal adhesions and cell movement through interaction with focal adhesion kinase. It can also bind to the cytoplasmic tail of membrane type 1 matrix metalloproteinase, a potent invasion-promoting protease, and play a key role in regulating multiple aspects of cancer cell migration and invasion. ZF21 contains a FYVE domain, which corresponds to this model.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 85719309 528 DKEKPGCKSCGETFNsITKRRYRCKLCGEVICRKCSEFKAENSKQS-----RVCREC 579
Cdd:cd15727   7 DKECPVCMSCKKKFD-FFKRRHHCRRCGKCFCSDCCSNKVPLPRMCfvdpvRVCNEC 62