FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6 pleckstrin homology (PH) domain, C-terminus; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635 1312 MSGYLYRSKGSKKPWKHLWFVIKNKVLYTYAASEDVAALESQPLLGFTVAQVKD--EHSDPRVFQLLHKGLLFYVFKADD 1389
Cdd:cd13237     1 MSGYLQRRKKSKKSWKRLWFVLKDKVLYTYKASEDVVALESVPLLGFTVVTIDEsfEEDESLVFQLLHKGQLPIIFRADD 80

                          90
                  ....*....|.
gi 212549635 1390 AHSTQRWIDAF 1400
Cdd:cd13237    81 AETAQRWIEAL 91

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 212549635 1193 PIWIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYLKGQPARVCELCF 1253
Cdd:cd15743     1 PIWIPDSRVTMCMICTSEFTVTWRRHHCRACGKVVCGSCSSNKAPLEYLKNKSARVCDECF 61

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6 pleckstrin homology (PH) domain, C-terminus; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635 1312 MSGYLYRSKGSKKPWKHLWFVIKNKVLYTYAASEDVAALESQPLLGFTVAQVKD--EHSDPRVFQLLHKGLLFYVFKADD 1389
Cdd:cd13237     1 MSGYLQRRKKSKKSWKRLWFVLKDKVLYTYKASEDVVALESVPLLGFTVVTIDEsfEEDESLVFQLLHKGQLPIIFRADD 80

                          90
                  ....*....|.
gi 212549635 1390 AHSTQRWIDAF 1400
Cdd:cd13237    81 AETAQRWIEAL 91

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 212549635    852 IAKEIMSSEKVFVDVLKLLHIDFRGAVahasrQLGKPVIEDRILNQILYYLPQLYELNRDLLKELEERMLSWAE-QQRIA 930
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPL-----KKELKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDsVERIG 75

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635    931 DIFVKKGPYLKMYSMYIKEFDKNIALLdEQCKKNSGFATVVREFEMSPRCANLALKHYLLKPVQRIPQYRLLLTDYLKNL 1010
Cdd:smart00325   76 DVFLKLEEFFKIYSEYCSNHPDALELL-KKLKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                           170       180
                    ....*....|....*....|....*.
gi 212549635   1011 LEDSVDHRDTQDALAVVIEVANHAND 1036
Cdd:smart00325  155 PEDHEDREDLKKALKAIKELANQVNE 180

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 212549635  850 HHIAKEIMSSEKVFVDVLKLLHIDFRGAVahasRQLGKPVIEDrILNQILYYLPQLYELNRDLLKELEERMLSW-AEQQR 928
Cdd:cd00160     2 QEVIKELLQTERNYVRDLKLLVEVFLKPL----DKELLPLSPE-EVELLFGNIEEIYEFHRIFLKSLEERVEEWdKSGPR 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635  929 IADIFVKKGPYLKMYSMYIKEFDKNIALLDEQCKKNSGFATVVREFEmsPRCANLALKHYLLKPVQRIPQYRLLLTDYLK 1008
Cdd:cd00160    77 IGDVFLKLAPFFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLEKAE--SECGRLKLESLLLKPVQRLTKYPLLLKELLK 154

                         170       180
                  ....*....|....*....|....*..
gi 212549635 1009 NLLEDSVDHRDTQDALAVVIEVANHAN 1035
Cdd:cd00160   155 HTPDGHEDREDLKKALEAIKEVASQVN 181

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        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 212549635   1192 APIWIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYL-KGQPARVCELCFQELQK 1258
Cdd:smart00064    1 RPHWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLgIERPVRVCDDCYENLNG 68

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 212549635   1067 FLKEGILMKLS---RKVMQPRMIFLFNDALLYTTPMQSGM-YKLNNMLSLAGMKVRKPTQEA---YQNELKIESVER-SF 1138
Cdd:smart00233    1 VIKEGWLYKKSgggKKSWKKRYFVLFNSTLLYYKSKKDKKsYKPKGSIDLSGCTVREAPDPDsskKPHCFEIKTSDRkTL 80

                            90       100
                    ....*....|....*....|.
gi 212549635   1139 ILSASSASERDDWLEAISRAI 1159
Cdd:smart00233   81 LLQAESEEEREKWVEALRKAI 101

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635  1069 KEGILMKLSRKVM---QPRMIFLFNDALLYTTPMQSGM-YKLNNMLSLAGMKVRKPTQEAYQNE-------LKIESVERS 1137
Cdd:pfam00169    3 KEGWLLKKGGGKKkswKKRYFVLFDGSLLYYKDDKSGKsKEPKGSISLSGCEVVEVVASDSPKRkfcfelrTGERTGKRT 82

                           90       100
                   ....*....|....*....|...
gi 212549635  1138 FILSASSASERDDWLEAISRAIE 1160
Cdd:pfam00169   83 YLLQAESEEERKDWIKAIQSAIR 105

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 212549635 1054 LSGHHEIVQPGRVFLKEGILMKLSRKVMQPRMIFLFNDALLYTTPMQS-GMYKLNNMLSLAGMKVRKPTQEAYQNELKIE 1132
Cdd:cd13389     1 LLGQYNIVKPGRKLIKEGELMKVSRKEMQPRYFFLFNDCLLYTTPVQSsGMLKLNNELPLSGMKVKLPEDEEYSNEFQII 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 212549635 1133 SVERSFILSASSASERDDWLEAISRAIEEYAKKRITFCPSRS 1174
Cdd:cd13389    81 STKRSFTLIASSEEERDEWVKALSRAIEEHTKKQRTFAENVS 122

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 212549635   852 IAKEIMSSEKVFVDVLKLLHIDFRgavahasRQLGKPVIE-DRILNQILYYLPQLYELNRDLLkeLEERMLSWAEQQRIA 930
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFL-------PPNSKPLSEsEEEIKTIFSNIEEIYELHRQLL--LEELLKEWISIQRIG 71

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635   931 DIFVKKGPYLKMYSMYIKEFDKNIALLDEQCKKNSGFATVVREFEMSPRCANLALKHYLLKPVQRIPQYRLLLTDYLKNL 1010
Cdd:pfam00621   72 DIFLKFAPGFKVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHT 151

                          170       180
                   ....*....|....*....|....*
gi 212549635  1011 LEDSVDHRDTQDALAVVIEVANHAN 1035
Cdd:pfam00621  152 PPDHPDYEDLKKALEAIKEVAKQIN 176

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia protein 5, 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. 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 212549635 1056 GHHEIVQPGRVFLKEGILMKLSRKVMQPRMIFLFNDALLYTTPMQSGMYKLNNMLSLAGMKVRKPTQEAYQNELKIESVE 1135
Cdd:cd15792     3 GQRDLLQPGREFVKEGTLMKVSGKNRHPRHLFLMNDVLLYTYPQKDGKYRLKNTLAVSGMKVSRPVIEKAQNVLKIEVSE 82

                          90       100       110
                  ....*....|....*....|....*....|....
gi 212549635 1136 RSFILSASSASERDDWLEAISRAIEEYAKKRITF 1169
Cdd:cd15792    83 VCLTLSASSCSERDEWYSCLSRTIPDDYKAQNAS 116

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 212549635 1069 KEGILMKLSRK--VMQPRMIFLFNDALLYTTPMQSGM---YKLNNMLSLAGMKVRKPTQEAYQNELKIESVERSFILSAS 1143
Cdd:cd13328     1 KEGQILKLSAKngTPQPRYLFLFNDMLLYCVPKLSLVgqkFSVRNRLDVAGMKVREPVNENYPHTFKISGKERSLELQAS 80

                          90
                  ....*....|..
gi 212549635 1144 SASERDDWLEAI 1155
Cdd:cd13328    81 SAEEKDEWIQAI 92

FYVE domain found in endofin and similar proteins; Endofin, also termed zinc finger FYVE domain-containing protein 16 (ZFY16), or endosome-associated FYVE domain protein, is a FYVE domain-containing protein that is localized to EEA1-containing endosomes. It is regulated by phosphoinositol lipid and engaged in endosome-mediated receptor modulation. Endofin is involved in Bone morphogenetic protein (BMP) signaling through interacting with Smad1 preferentially and enhancing Smad1 phosphorylation and nuclear localization upon BMP stimulation. It also functions as a scaffold protein that brings Smad4 to the proximity of the receptor complex in Transforming growth factor (TGF)-beta signaling. Moreover, endofin is a novel tyrosine phosphorylation target downstream of epidermal growth factor receptor (EGFR) in EGF-signaling. In addition, endofin plays a role in endosomal trafficking by recruiting cytosolic TOM1, an important molecule for membrane recruitment of clathrin, onto endosomal membranes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 212549635 1189 GAKAPIWIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYLKGQPARVCELCFQEL 1256
Cdd:cd15729     1 GKVAPVWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEYLDNKEARVCVPCYQTL 68

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        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 212549635   1192 APIWIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYL-KGQPARVCELCFQELQK 1258
Cdd:smart00064    1 RPHWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLgIERPVRVCDDCYENLNG 68

FYVE-like domain found in FYVE, RhoGEF and PH domain-containing protein 5 (FGD5) and similar proteins; FGD5, also termed zinc finger FYVE domain-containing protein 23, is an endothelial cell (EC)-specific guanine nucleotide exchange factor (GEF) that regulates endothelial adhesion, survival, and angiogenesis by modulating phosphatidylinositol 3-kinase signaling. It functions as a novel genetic regulator of vascular pruning by activation of endothelial cell-targeted apoptosis. FGD5 is a homologue of FGD1 and contains a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. The FYVE domain of FGD5 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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 212549635 1193 PIWIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYLKGQPARVCELCFQELQK 1258
Cdd:cd15742     1 PTLVPVSHVMMCMNCGSDFTLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRPAKVCDGCFAELRK 66

Phafin2 (also called EAPF, FLJ13187, ZFYVE18 or PLEKHF2) Pleckstrin Homology (PH) domain; Phafin2 is differentially expressed in the liver cancer cell and regulates the structure and function of the endosomes through Rab5-dependent processes. Phafin2 modulates the cell's response to extracellular stimulation by modulating the receptor density on the cell surface. Phafin2 contains a PH domain and a FYVE domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635 1043 NFQKLMQIQYSLSGH-HEIVQPGRVFLKEGILMKLSRKVMQPRMIFLFNDALLYTT-PMQSGMYKLNNMLSLAGMKVR-K 1119
Cdd:cd01218     5 NRRRIAAVESCFGGSgQPLVKPGRVLVGEGVLTKVCRKKPKPRQFFLFNDILVYGSiVINKKKYNKQRIIPLEDVKIEdL 84

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 212549635 1120 PTQEAYQNELKIESVERSFILSASSASERDDWLEAISRA 1158
Cdd:cd01218    85 EDTGELKNGWQIISPKKSFVVYAATATEKSEWMDHINKC 123

FYVE domain found in FYVE domain-containing protein 26 (ZFY26 or ZFYVE26); ZFY26, also termed FYVE domain-containing centrosomal protein (FYVE-CENT), or spastizin, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein that localizes to the centrosome and midbody. ZFY26 and its interacting partners TTC19 and KIF13A are required for cytokinesis. It also interacts with Beclin 1, a subunit of class III phosphatidylinositol 3-kinase complex, and may have potential implications for carcinogenesis. In addition, it has been considered as the causal agent of a rare form of hereditary spastic paraplegia. ZFY26 contains a FYVE domain that is important for targeting of FYVE-CENT to the midbody.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 212549635 1195 WIPDTRATMCMICTSE-FTLTWRRHHCRACGKIVCQACSSNKCGLDYLKGQPARVCELCFQ 1254
Cdd:cd15724     1 WVPDEAVSVCMVCQVErFSMFNRRHHCRRCGRVVCSSCSTKKMLVEGYRENPVRVCDQCYE 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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 212549635 1193 PIWIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYLKgQPARVCELCFQEL 1256
Cdd:cd15730     1 RKWADDEEVQNCMACGKGFSVTVRKHHCRQCGNIFCNECSSKTATTPSSK-KPVRVCDACFDDL 63

FYVE domain found in protein containing both PH and FYVE domains 1 (phafin-1) and similar proteins; Phafin-1, also termed lysosome-associated apoptosis-inducing protein containing PH (pleckstrin homology) and FYVE domains (LAPF), or pleckstrin homology domain-containing family F member 1 (PKHF1), or PH domain-containing family F member 1, or apoptosis-inducing protein, or PH and FYVE domain-containing protein 1, or zinc finger FYVE domain-containing protein 15, is a representative of a novel family of PH and FYVE domain-containing proteins called phafins. It is a ubiquitously expressed pro-apoptotic protein via translocating to lysosomes, facilitating apoptosis induction through a lysosomal-mitochondrial apoptotic pathway.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 212549635 1195 WIPDTRATMCMICT-SEFTLTWRRHHCRACGKIVCQACSSNKCGLDYLKGQPARVCELCFQEL 1256
Cdd:cd15754     2 WIPDKATDICMRCTqTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLSPKPVRVCSLCYRKL 64

FYVE domain found in protein containing both PH and FYVE domains 2 (phafin-2) and similar proteins; Phafin-2, also termed endoplasmic reticulum-associated apoptosis-involved protein containing PH and FYVE domains (EAPF), or pleckstrin homology domain-containing family F member 2 (PKHF2), or PH domain-containing family F member 2, or PH and FYVE domain-containing protein 2, or zinc finger FYVE domain-containing protein 18, is a ubiquitously expressed endoplasmic reticulum-associated protein that facilitates tumor necrosis factor alpha (TNF-alpha)-triggered cellular apoptosis through endoplasmic reticulum (ER)-mitochondrial apoptotic pathway. It is an endosomal phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) effector, as well as an interactor of the endosomal-tethering protein EEA1. It regulates endosome fusion upstream of Rab5. Phafin-2 also functions as a novel regulator of endocytic epidermal growth factor receptor (EGFR) degradation through a role in endosomal fusion.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 212549635 1194 IWIPDTRATMCMICTS-EFTLTWRRHHCRACGKIVCQACSSNKCGLDYLKGQPARVCELCFQEL 1256
Cdd:cd15755     1 VWVPDSEATVCMRCQKaKFTPVNRRHHCRKCGFVVCGPCSEKKFLLPSQSSKPVRVCDFCYDLL 64

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 212549635 1303 VSANTEDSTMSGYLYRSkGSKKPWKHLWFVIKNK---VLYTYAASEDVAALESQPLLGFTVAQVKDE--HSDPRVFQLLH 1377
Cdd:cd13236     1 ASAVPENSLLCGFLQYS-EKGKTWQKVWCVIPRTeplVLYLYGAPQDVRAQRTIPLPGCEVTVPPPEerLDGRHVFKLSQ 79

                          90       100
                  ....*....|....*....|..
gi 212549635 1378 KGLLFYvFKADDAHSTQRWIDA 1399
Cdd:cd13236    80 SKQSHY-FSAESEELQQRWLEA 100

FYVE domain found in myotubularin-related protein 4 (MTMR4) and similar proteins; MTMR4, also termed FYVE domain-containing dual specificity protein phosphatase 2 (FYVE-DSP2), or zinc finger FYVE domain-containing protein 11, is an dual specificity protein phosphatase that specifically dephosphorylates phosphatidylinositol 3-phosphate (PtdIns3P or PI3P). It is localizes to early endosomes, as well as to Rab11- and Sec15-positive recycling endosomes, and regulates sorting from early endosomes. Moreover, MTMR4 is preferentially associated with and dephosphorylated the activated regulatory Smad proteins (R-Smads) in cytoplasm to keep transforming growth factor (TGF) beta signaling in homeostasis. It also functions as an essential negative modulator for the homeostasis of bone morphogenetic protein (BMP)/decapentaplegic (Dpp) signaling. In addition, MTMR4 acts as a novel interactor of the ubiquitin ligase Nedd4 (neural-precursor-cell-expressed developmentally down-regulated 4) and may play a role in the biological process of muscle breakdown. MTMR4 contains an N-terminal PH-GRAM (PH-G) domain, a MTM phosphatase domain, a coiled-coil region, and a C-terminal FYVE domain.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635 1195 WIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYLK-GQPARVCELCF 1253
Cdd:cd15733     1 WVPDHAASHCFGCDCEFWLAKRKHHCRNCGNVFCADCSNYKLPIPDEQlYDPVRVCNSCY 60

FYVE domain found in myotubularin-related protein 3 (MTMR3) and similar proteins; MTMR3, also termed Myotubularin-related phosphatase 3, or FYVE domain-containing dual specificity protein phosphatase 1 (FYVE-DSP1), or zinc finger FYVE domain-containing protein 10, is a ubiquitously expressed phosphoinositide 3-phosphatase specific for phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) and PIKfyve, which produces PtdIns(3,5)P2 from PtdIns3P. It regulates cell migration through modulating phosphatidylinositol 5-phosphate (PtdIns5P) levels. MTMR3 contains an N-terminal PH-GRAM (PH-G) domain, a MTM phosphatase domain, a coiled-coil region, and a C-terminal FYVE domain. Unlike conventional FYVE domains, the FYVE domain of MTMR3 neither confers endosomal localization nor binds to PtdIns3P. It is also not required for the enzyme activity of MTMR3. In contrast, the PH-G domain binds phosphoinositides.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635 1195 WIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYLKG-QPARVCELCF 1253
Cdd:cd15732     2 WVPDHLAASCYGCEREFWLASRKHHCRNCGNVFCGSCCNQKLPVPSQQLfEPSRVCKSCF 61

FYVE domain found in Schizosaccharomyces pombe vacuolar protein sorting-associated protein 27 (spVps27p) and similar proteins; spVps27p, also termed suppressor of ste12 deletion protein 4 (Sst4p), is a conserved homolog of budding Saccharomyces cerevisiae Vps27 and of mammalian Hrs. It functions as a downstream factor for phosphatidylinositol 3-kinase (PtdIns 3-kinase) in forespore membrane formation with normal morphology. It colocalizes and interacts with Hse1p, a homolog of Saccharomyces cerevisiae Hse1p and of mammalian STAM, to form a complex whose ubiquitin-interacting motifs (UIMs) are important for sporulation. spVps27p contains a VHS (Vps27p/Hrs/Stam) domain, a FYVE domain, and two UIMs.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 212549635 1193 PIWIPdtrATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYLK-GQPARVCELCF 1253
Cdd:cd15735     1 PEWVD---SDVCMRCRTAFTFTNRKHHCRNCGGVFCQQCSSKSLPLPHFGiNQPVRVCDGCY 59

FYVE domain found in RUN and FYVE domain-containing protein 1 (RUFY1) and similar proteins; RUFY1, also termed FYVE-finger protein EIP1, or La-binding protein 1, or Rab4-interacting protein (Rabip4), or Zinc finger FYVE domain-containing protein 12 (ZFY12), a human homologue of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY1 contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 212549635 1191 KAPIWIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGL-DYLKgqPARVCELC 1252
Cdd:cd15758     2 KGHAWLKDDEATHCKQCEKEFSISRRKHHCRNCGHIFCNTCSSNELALpSYPK--PVRVCDSC 62

FYVE domain found in hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs) and similar proteins; Hrs, also termed protein pp110, is a tyrosine phosphorylated protein that plays an important role in the signaling pathway of HGF. It is localized to early endosomes and an essential component of the endosomal sorting and trafficking machinery. Hrs interacts with hypertonia-associated protein Trak1, a novel regulator of endosome-to-lysosome trafficking. It can also forms an Hrs/actinin-4/BERP/myosin V protein complex that is required for efficient transferrin receptor (TfR) recycling but not for epidermal growth factor receptor (EGFR) degradation. Moreover, Hrs, together with STAM proteins, STAM1 and STAM2, and EPs15, forms a multivalent ubiquitin-binding complex that sorts ubiquitinated proteins into the multivesicular body pathway, and plays a regulatory role in endocytosis/exocytosis. Furthermore, Hrs functions as an interactor of the neurofibromatosis 2 tumor suppressor protein schwannomin/merlin. It is also involved in the inhibition of citron kinase-mediated HIV-1 budding. Hrs contains a single ubiquitin-interacting motif (UIM) that is crucial for its function in receptor sorting, and a FYVE domain that harbors double Zn2+ binding sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 212549635 1204 CMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGL-DYLKGQPARVCELCFQEL 1256
Cdd:cd15720     8 CHRCRVQFGVFQRKHHCRACGQVFCGKCSSKSSTIpKFGIEKEVRVCDPCYEKL 61

FYVE domain found in FYVE finger-containing Rab5 effector protein rabenosyn-5 (Rbsn-5) and similar proteins; Rbsn-5, also termed zinc finger FYVE domain-containing protein 20, is a novel Rab5 effector that is complexed to the Sec1-like protein VPS45 and recruited in a phosphatidylinositol-3-kinase-dependent fashion to early endosomes. It also binds to Rab4 and EHD1/RME-1, two regulators of the recycling route, and is involved in cargo recycling to the plasma membrane. Moreover, Rbsn-5 regulates endocytosis at the apical side of the wing epithelium and plays a role of the apical endocytic trafficking of Fmi in the establishment of planar cell polarity (PCP).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 212549635 1195 WIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSnkcGLDYlkgqPARVCELCFQELQK 1258
Cdd:cd15716     4 WVNDSDVPFCPDCGKKFNLARRRHHCRLCGSIMCNKCSQ---FLPL----HIRCCHHCKDLLER 60

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 1-4 and similar proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. They play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway. FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635 1068 LKEGILMKLSRKV--MQPRMIFLFNDALLYTTP---MQSGMYKLNNMLSLAGMKVRKPTQEAYQNELKIESVERSFILSA 1142
Cdd:cd13388     2 IKEGKILKISARNgdTQERYLFLFNDMLLYCSPrlrLIGQKYKVRARFDVDGMQVLEGDNLETPHTFYVRGKQRSLELQA 81

                          90
                  ....*....|...
gi 212549635 1143 SSASERDDWLEAI 1155
Cdd:cd13388    82 STQEEKAEWVDAI 94

FYVE domain found in RUN and FYVE domain-containing protein 2 (RUFY2) and similar proteins; RUFY2, also termed Rab4-interacting protein related, is a novel embryonic factor that contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between. It is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 212549635 1194 IWIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKCGLDYlKGQPARVCELC 1252
Cdd:cd15759     3 VWLKDKEATHCKLCEKEFSLSKRKHHCRNCGEIFCNACSDNELPLPS-SPKPVRVCDSC 60

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635 1312 MSGYLY-RSKGSKKPWKHLWFVIKNKVLYTYAASEDV--AALESQPLLGFTVAQVKDEHSDPRVFQLLHKGLLFYVFKAD 1388
Cdd:cd00821     1 KEGYLLkRGGGGLKSWKKRWFVLFEGVLLYYKSKKDSsyKPKGSIPLSGILEVEEVSPKERPHCFELVTPDGRTYYLQAD 80

                          90
                  ....*....|..
gi 212549635 1389 DAHSTQRWIDAF 1400
Cdd:cd00821    81 SEEERQEWLKAL 92

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212549635 1069 KEGILMKLSRKVM---QPRMIFLFNDALLYTTPMQSGMYKLNNMLSLAG-MKVRKPTQEAYQNELKIE-SVERSFILSAS 1143
Cdd:cd00821     1 KEGYLLKRGGGGLkswKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGiLEVEEVSPKERPHCFELVtPDGRTYYLQAD 80