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 1831513559 407 FQCQFNVLEPGRVLIRQSEVMKQTRKELQPRYLVLFTDYLWICR-VSSSGQFDINRSYriPLEYMKFERMEEDERIRCLQ 485
Cdd:cd13389     1 LLGQYNIVKPGRKLIKEGELMKVSRKEMQPRYFFLFNDCLLYTTpVQSSGMLKLNNEL--PLSGMKVKLPEDEEYSNEFQ 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1831513559 486 IRSRVKSALIIFSSEKERNQWTDDLTKAQYDRKSYKRRQSTAVQRH 531
Cdd:cd13389    79 IISTKRSFTLIASSEEERDEWVKALSRAIEEHTKKQRTFAENVSGV 124

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        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513559  612 KPVWLPDNISNEClmEGCSTEFNIINRRHHCRDCGWLICKFCKGQAPLSKYD--FTKQNVCSECFDRHYK 679
Cdd:smart00064   1 RPHWIPDEEVSNC--MGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLgiERPVRVCDDCYENLNG 68

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 1831513559 407 FQCQFNVLEPGRVLIRQSEVMKQTRKELQPRYLVLFTDYLWICR-VSSSGQFDINRSYriPLEYMKFERMEEDERIRCLQ 485
Cdd:cd13389     1 LLGQYNIVKPGRKLIKEGELMKVSRKEMQPRYFFLFNDCLLYTTpVQSSGMLKLNNEL--PLSGMKVKLPEDEEYSNEFQ 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1831513559 486 IRSRVKSALIIFSSEKERNQWTDDLTKAQYDRKSYKRRQSTAVQRH 531
Cdd:cd13389    79 IISTKRSFTLIASSEEERDEWVKALSRAIEEHTKKQRTFAENVSGV 124

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 1831513559  198 AAVEFLKVQNNYVQYLKEMAVLYpeyMERFGKRVgrdLLASHNGHENVVLQIkkimVQILPIHEMLLKEIDKVCSNWDSR 277
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVF---LKPLKKEL---KLLSPNELETLFGNI----EEIYEFHRDFLDELEERIEEWDDS 70

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513559  278 YPNMSKTIGTFADFLKCCQPFLDNKADFLnKLLQLRNEDKEFDEATYMFETEVFKRGKKgaVIQQLDQVHQNFMRYKLLM 357
Cdd:smart00325  71 VERIGDVFLKLEEFFKIYSEYCSNHPDAL-ELLKKLKKNPRFQKFLKEIESSPQCRRLT--LESLLLKPVQRLTKYPLLL 147

                          170       180       190
                   ....*....|....*....|....*....|...
gi 1831513559  358 LRYSEYLIDDCDEKEKAQEAIQKLENVTQAVNQ 390
Cdd:smart00325 148 KELLKHTPEDHEDREDLKKALKAIKELANQVNE 180

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1831513559 613 PVWLPDNISNECLMegCSTEFNIINRRHHCRDCGWLICKFC---KGQAPLSKYDFTKQNVCSECFDR 676
Cdd:pfam01363   1 PVWVPDSSATVCMI--CSKPFTFFRRRHHCRNCGRVFCSACsskKISLLPELGSNKPVRVCDACYDT 65

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 1831513559  420 LIRQSEVMKQT---RKELQPRYLVLFTDYLWICRvSSSGQFDINRSYRIPLEYMKFERMEEDERI---RCLQIRSRVKSA 493
Cdd:smart00233   1 VIKEGWLYKKSgggKKSWKKRYFVLFNSTLLYYK-SKKDKKSYKPKGSIDLSGCTVREAPDPDSSkkpHCFEIKTSDRKT 79

                           90       100
                   ....*....|....*....|...
gi 1831513559  494 LII-FSSEKERNQWTDDLTKAQY 515
Cdd:smart00233  80 LLLqAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513559 420 LIRQSEVMKQT---RKELQPRYLVLFTDYLWICRVSSSGQFDINRSYrIPL---EYMKFERMEEDERIRCLQIR----SR 489
Cdd:pfam00169   1 VVKEGWLLKKGggkKKSWKKRYFVLFDGSLLYYKDDKSGKSKEPKGS-ISLsgcEVVEVVASDSPKRKFCFELRtgerTG 79

                          90       100
                  ....*....|....*....|....*.
gi 1831513559 490 VKSALIIFSSEKERNQWTDDLTKAQY 515
Cdd:pfam00169  80 KRTYLLQAESEEERKDWIKAIQSAIR 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 1831513559 407 FQCQFNVLEPGRVLIRQSEVMKQTRKELQPRYLVLFTDYLWICR-VSSSGQFDINRSYriPLEYMKFERMEEDERIRCLQ 485
Cdd:cd13389     1 LLGQYNIVKPGRKLIKEGELMKVSRKEMQPRYFFLFNDCLLYTTpVQSSGMLKLNNEL--PLSGMKVKLPEDEEYSNEFQ 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1831513559 486 IRSRVKSALIIFSSEKERNQWTDDLTKAQYDRKSYKRRQSTAVQRH 531
Cdd:cd13389    79 IISTKRSFTLIASSEEERDEWVKALSRAIEEHTKKQRTFAENVSGV 124

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 1831513559  198 AAVEFLKVQNNYVQYLKEMAVLYpeyMERFGKRVgrdLLASHNGHENVVLQIkkimVQILPIHEMLLKEIDKVCSNWDSR 277
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVF---LKPLKKEL---KLLSPNELETLFGNI----EEIYEFHRDFLDELEERIEEWDDS 70

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513559  278 YPNMSKTIGTFADFLKCCQPFLDNKADFLnKLLQLRNEDKEFDEATYMFETEVFKRGKKgaVIQQLDQVHQNFMRYKLLM 357
Cdd:smart00325  71 VERIGDVFLKLEEFFKIYSEYCSNHPDAL-ELLKKLKKNPRFQKFLKEIESSPQCRRLT--LESLLLKPVQRLTKYPLLL 147

                          170       180       190
                   ....*....|....*....|....*....|...
gi 1831513559  358 LRYSEYLIDDCDEKEKAQEAIQKLENVTQAVNQ 390
Cdd:smart00325 148 KELLKHTPEDHEDREDLKKALKAIKELANQVNE 180

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1831513559 613 PVWLPDNISNECLMegCSTEFNIINRRHHCRDCGWLICKFC---KGQAPLSKYDFTKQNVCSECFDR 676
Cdd:pfam01363   1 PVWVPDSSATVCMI--CSKPFTFFRRRHHCRNCGRVFCSACsskKISLLPELGSNKPVRVCDACYDT 65

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 1831513559 613 PVWLPDNISNECLmeGCSTEFNIINRRHHCRDCGWLICKFC-KGQAPLSKYDFTKQNVCSECF 674
Cdd:cd15743     1 PIWIPDSRVTMCM--ICTSEFTVTWRRHHCRACGKVVCGSCsSNKAPLEYLKNKSARVCDECF 61

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 1831513559 611 IKPVWLPDNISNECLmeGCSTEFNIINRRHHCRDCGWLICKFCKGQ-APLSKYDFTKQNVCSECF 674
Cdd:cd15729     3 VAPVWVPDSEAPNCM--QCEVKFTFTKRRHHCRACGKVLCSACCSLkARLEYLDNKEARVCVPCY 65

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 1831513559 414 LEPGRVLIRQSEVMKQTRKELQPRYLVLFTDYLwICRVSSSGQFDINRSYRIPLEYMKFERMEEDERIR-CLQIRSRVKS 492
Cdd:cd01218    24 VKPGRVLVGEGVLTKVCRKKPKPRQFFLFNDIL-VYGSIVINKKKYNKQRIIPLEDVKIEDLEDTGELKnGWQIISPKKS 102

                          90       100
                  ....*....|....*....|.
gi 1831513559 493 ALIIFSSEKERNQWTDDLTKA 513
Cdd:cd01218   103 FVVYAATATEKSEWMDHINKC 123

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 1831513559 413 VLEPGRVLIRQSEVMKQTRKELQPRYLVLFTDYLWICRVSSSGQFDINRsyRIPLEYMKFERMEEDERIRCLQIRSRVKS 492
Cdd:cd15793     7 IVQPGRVFLKEGTLMKLSRKVMQPRMFFLFNDALLYTTPVQSGMYKLNN--MLSLAGMKVSKPSQEAYQNELNIESVERS 84

                          90       100
                  ....*....|....*....|....*...
gi 1831513559 493 ALIIFSSEKERNQWTDDLTKA--QYDRK 518
Cdd:cd15793    85 FILSASSATERDEWLEAISRAieEYAKK 112

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 1; Members here include FARP1 (also called Chondrocyte-derived ezrin-like protein; PH domain-containing family C member 2), FARP2 (also called FIR/FERM domain including RhoGEF; FGD1-related Cdc42-GEF/FRG), and FARP6 (also called Zinc finger FYVE domain-containing protein 24). They are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. Little is known about FARP1 and FARP6, though FARP1 has increased expression in differentiated chondrocytes. FARP2 is thought to regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac. It is found in brain, lung, and testis, as well as embryonic hippocampal and cortical neurons. FARP1 and FARP2 are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. FARP6 is composed of Dbl-homology (DH), and two C-terminal PH domains separated by a FYVE domain. This hierarchy contains the first PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513559 413 VLEPGRVLIRQSEVMKQTRKELQPRYLVLFTDYL-WICR-VSSSGQFDINRsyRIPLEYMKFERME-EDERIRCLQIRSR 489
Cdd:cd01220     1 LVQPGREFIREGCLQKLSKKGLQQRMFFLFSDVLlYTSRsPTPSLQFKVHG--QLPLRGLMVEESEpEWGVAHCFTIYGG 78

                          90       100
                  ....*....|....*....|....
gi 1831513559 490 VKSALIIFSSEKERNQWTDDLTKA 513
Cdd:cd01220    79 NRALTVAASSEEEKERWLEDLQRA 102

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1831513559 613 PVWLPDNISNECLMegCSTEFN-IINRRHHCRDCGWLICKFCKGQAPLSKYDFTKQN-VCSECFD 675
Cdd:cd15741     1 PRWVRDNEVTMCMR--CKEPFNaLTRRRHHCRACGYVVCWKCSDYKATLEYDGNKLNrVCKHCYV 63

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 1831513559 615 WLPDNISNECLmeGCSTEFNIINRRHHCRDCGWLICKFCKGQ-APL-SKYDFTKQNVCSECF 674
Cdd:cd15732     2 WVPDHLAASCY--GCEREFWLASRKHHCRNCGNVFCGSCCNQkLPVpSQQLFEPSRVCKSCF 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 1831513559 613 PVWLPDNISNECLmeGCSTEFNIINRRHHCRDCGWLICKFCKG-QAPLSKYDfTKQNVCSECFD 675
Cdd:cd15730     1 RKWADDEEVQNCM--ACGKGFSVTVRKHHCRQCGNIFCNECSSkTATTPSSK-KPVRVCDACFD 61

FYVE domain found in metazoan PIKfyve, fungal and plant Fab1, and similar proteins; PIKfyve, also termed FYVE finger-containing phosphoinositide kinase, or 1-phosphatidylinositol 3-phosphate 5-kinase, or phosphatidylinositol 3-phosphate 5-kinase (PIP5K3), or phosphatidylinositol 3-phosphate 5-kinase type III (PIPkin-III or type III PIP kinase), is a phosphoinositide 5-kinase that forms a complex with its regulators, the scaffolding protein Vac14 and the lipid phosphatase Fig4. The complex is responsible for synthesizing phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] from phosphatidylinositol 3-phosphate (PtdIns3P or PI3P). Then phosphatidylinositol-5-phosphate (PtdIns5P) is generated directly from PtdIns(3,5)P2. PtdIns(3,5)P2 and PtdIns5P regulate endosomal trafficking and responses to extracellular stimuli. At this point, PIKfyve is vital in early embryonic development. Moreover, PIKfyve forms a complex with ArPIKfyve (associated regulator of PIKfyve) and SAC3 at the endomembranes, which plays a role in receptor tyrosine kinase (RTK) degradation. The phosphorylation of PIKfyve by AKT can facilitate Epidermal growth factor receptor (EGFR) degradation. In addition, PIKfyve may participate in the regulation of the glutamate transporters EAAT2, EAAT3 and EAAT4, and the cystic fibrosis transmembrane conductance regulator (CFTR). It is also essential for systemic glucose homeostasis and insulin-regulated glucose uptake/GLUT4 translocation in skeletal muscle. It can be activated by protein kinase B (PKB/Akt) and further up-regulates human ether-a-go-go (hERG) channels. This family also includes the yeast and plant orthologs of human PIKfyve, Fab1. PIKfyve and its orthologs share a similar architecture. They contain an N-terminal FYVE domain, a middle region related to the CCT/TCP-1/Cpn60 chaperonins that are involved in productive folding of actin and tubulin, a second middle domain that contains a number of conserved cysteine residues (CCR) unique to this family, and a C-terminal lipid kinase domain related to PtdInsP kinases.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1831513559 615 WLPDNISNECLmeGCSTEFNIINRRHHCRDCGWLIC-KFCKGQAPLSKYDFT-KQNVCSECF 674
Cdd:cd15725     2 WMPDSSCKECY--ECSEKFTTFRRRHHCRLCGQIFCsRCCNQEIPGKFIGYPgDLRVCTYCC 61

FYVE domain found in FYVE and coiled-coil domain-containing protein 1 (FYCO1) and similar proteins; FYCO1, also termed zinc finger FYVE domain-containing protein 7, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding protein that is associated with the exterior of autophagosomes and mediates microtubule plus-end-directed vesicle transport. It acts as an effector of GTP-bound Rab7, a GTPase that recruits FYCO1 to autophagosomes and has been implicated in autophagosome-lysosomal fusion. FYCO1 also interacts with two microtubule motor proteins, kinesin (KIF) 5B and KIF23, and thus functions as a platform for assembly of vesicle fusion and trafficking factors. FYCO1 contains an N-terminal alpha-helical RUN domain followed by a long central coiled-coil region, a FYVE domain and a GOLD (Golgi dynamics) domain in C-terminus.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513559 615 WLPDNISNECLmeGCSTEFNIINRRHHCRDCGWLICKFCKGQAPLSKYDFTKQNVCSECF 674
Cdd:cd15726     1 WQDDTDVTHCL--DCKSEFSWMVRRHHCRLCGRIFCYACSNFYVLTAHGGKKERCCKACF 58

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
                  ....*....|....*....|....*....|....*....
gi 1831513559 615 WLPDNISNEClmEGCSTEFNIINRRHHCRDCGWLICKFC 653
Cdd:cd15716     4 WVNDSDVPFC--PDCGKKFNLARRRHHCRLCGSIMCNKC 40

FYVE domain found in RUN and FYVE domain-containing protein RUFY1, RUFY2 and similar proteins; This family includes RUN and FYVE domain-containing protein RUFY1 and RUFY2. 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. RUFY2, also termed Rab4-interacting protein related, is a novel embryonic factor that is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions. Both RUFY1 and RUFY2 contain an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1831513559 615 WLPDNISNEClmEGCSTEFNIINRRHHCRDCGWLICKFC 653
Cdd:cd15721     1 WADDKEVTHC--QQCEKEFSLSRRKHHCRNCGGIFCNSC 37

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 1831513559 615 WLPDNISNEClmEGCSTEFNIINRRHHCRDCGWLICKFCKGQApLSKYDFTKQ-NVCSEC 673
Cdd:cd15758     6 WLKDDEATHC--KQCEKEFSISRRKHHCRNCGHIFCNTCSSNE-LALPSYPKPvRVCDSC 62

FYVE-related domain found in uncharacterized myotubularin-related proteins mainly from eumetazoa; This family includes a group of uncharacterized myotubularin-related proteins mainly found in eumetazoa. Although their biological functions remain unclear, they share similar domain architecture that consists of an N-terminal pleckstrin homology (PH) domain, a highly conserved region related to myotubularin proteins, a C-terminal FYVE domain. The model corresponds to the FYVE domain, which resembles the FYVE-related domain as it has an altered sequence in the basic ligand binding patch.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1831513559 622 NEClmeGCSTEFNIINRRHHCRDCGWLICKFC-KGQAPLSKYDF-TKQNVCSECF 674
Cdd:cd15738    10 TEC---SCSTPFDHFSKKHHCWRCGNVFCTRCiDKQRALPGHLSqRPVPVCRACY 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 1831513559 617 PDNISNECLMEgCSTEFNIINRRHHCRDCGWLICKFCKGQA-PLSKYDFTKQ-NVCSECF 674
Cdd:cd15735     1 PEWVDSDVCMR-CRTAFTFTNRKHHCRNCGGVFCQQCSSKSlPLPHFGINQPvRVCDGCY 59

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 1831513559 627 EGCSTEFN-IINRRHHCRDCGWLICKFCKGQAPLSkydfTKQN-VCSECF 674
Cdd:cd15740     9 KGCNESFNsITKRRHHCKQCGAVICGKCSEFKDLA----SRHNrVCRDCF 54

FYVE domains found in zinc finger FYVE domain-containing protein 1 (ZFYV1) and similar proteins; ZFYV1, also termed double FYVE-containing protein 1 (DFCP1), or SR3, or tandem FYVE fingers-1, is a novel tandem FYVE domain containing protein that binds phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) with high specificity over other phosphoinositides. The subcellular distribution of exogenously-expressed ZFYV1 to Golgi, endoplasmic reticulum (ER) and vesicular is governed in part by its FYVE domains but unaffected by wortmannin, a PI3-kinase inhibitor. In addition to C-terminal tandem FYVE domain, ZFYV1 contains an N-terminal putative C2H2 type zinc finger and a possible nucleotide binding P-loop.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1831513559 615 WLPDNISNECLMegCSTEFNIINRRHHCRDCGWLICKFC 653
Cdd:cd15734     2 WVPDSEIKECSV--CKRPFSPRLSKHHCRACGQGVCDDC 38

FYVE domain found in Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and FYVE-related domain 1 found in yeast protein VAC1 (Vac1p) and similar proteins; The family includes Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and protein VAC1 (Vac1p). 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. Vac1p, also termed vacuolar segregation protein Pep7p, or carboxypeptidase Y-deficient protein 7, or vacuolar protein sorting-associated protein 19 (Vps19p), or vacuolar protein-targeting protein 19, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding protein that interacts with a Rab GTPase, GTP-bound form of Vps21p, and a Sec1p homologue, Vps45p, to facilitate Vps45p-dependent vesicle-mediated vacuolar protein sorting. It also acts as a novel regulator of vesicle docking and/or fusion at the endosome and functions in vesicle-mediated transport of Golgi precursor carboxypeptidase Y (CPY), protease A (PrA), protease B (PrB), but not alkaline phosphatase (ALP) from the trans-Golgi network-like compartment (TGN) to the endosome. Vac1p contains an N-terminal classical TFIIIA-like zinc finger, two putative zinc-binding FYVE fingers, and a C-terminal coiled coil region. The FYVE domain in both Vps27p and Vac1p harbors a zinc-binding site composed of seven Cysteines and one Histidine, which is different from that of other FYVE domain containing proteins.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1831513559 629 CSTEFNIINRRHHCRDCGWLICK-FCKGQAPL--SKYD---FTKQNVCSECF 674
Cdd:cd15736     5 CSRTFNLNIRAHHCRKCGKLFCRrHLPNMIPLnlSAYDprnGKWYRCCHSCF 56

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 1831513559 248 QIKKI---MVQILPIHEMLLkeIDKVCSNWDSrYPNMSKTIGTFADFLKCCQPFLDNKADFLNKLLQLRNEDKEFdeATY 324
Cdd:pfam00621  37 EIKTIfsnIEEIYELHRQLL--LEELLKEWIS-IQRIGDIFLKFAPGFKVYSTYCSNYPKALKLLKKLLKKNPKF--RAF 111

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1831513559 325 MFETEVFKRGKKGAVIQQLDQVHQNFMRYKLLMLRYSEYLIDDCDEKEKAQEAIQKLENVTQAVN 389
Cdd:pfam00621 112 LEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPDHPDYEDLKKALEAIKEVAKQIN 176

Cloned out of library/PAK-interactive exchange factor pleckstrin homology (PH) domain; There are two forms of Pix proteins: alpha Pix (also called Rho guanine nucleotide exchange factor (GEF) 6/90Cool-2) and beta Pix (GEF7/p85Cool-1). betaPix contains an N-terminal SH3 domain, a RhoGEF/DH domain, a PH domain, a GIT1 binding domain (GBD), and a C-terminal coiled-coil (CC) domain. alphaPix differs in that it contains a calponin homology (CH) domain, which interacts with beta-parvin, N-terminal to the SH3 domain. alphaPix is an exchange factor for Rac1 and Cdc42 and mediates Pak activation on cell adhesion to fibronectin. Mutations in alphaPix can cause X-linked mental retardation. alphaPix also interacts with Huntington's disease protein (htt), and enhances the aggregation of mutant htt (muthtt) by facilitating SDS-soluble muthtt-muthtt interactions. The DH-PH domain of a Pix was required for its binding to htt. In the majority of Rho GEF proteins, the DH-PH domain is responsible for the exchange activity. 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 1831513559 421 IRQSEVMKQTRKELQPRYLVLFTDYLWICRVSSSGQFDInrsY--RIPLEYMKFERMEEDERIRC-LQIR-SRVKSALII 496
Cdd:cd01225     4 MSQVAVQNTGCQEKKERYFLLFPHVLLMLSASPRMSGFI---YegKLPLTGISVNRLEDTEGIKNaFEISgPLIERIVVI 80

                          90
                  ....*....|....*....
gi 1831513559 497 FSSEKERNQWTDDLTKAQY 515
Cdd:cd01225    81 CNSQQDQQEWLEHLQQQTK 99

RA and RhoGAP domain-containing protein Pleckstrin homology PH domain; RARhoGAP (also called Rho GTPase-activating protein 20 and ARHGAP20 ) is thought to function in rearrangements of the cytoskeleton and cell signaling events that occur during spermatogenesis. RARhoGAP was also shown to be activated by Rap1 and to induce inactivation of Rho, resulting in the neurite outgrowth. Recent findings show that ARHGAP20, even although it is located in the middle of the MDR on 11q22-23, is expressed at higher levels in chronic lymphocytic leukemia patients with 11q22-23 and/or 13q14 deletions and its expression pattern suggests a functional link between cases with 11q22-23 and 13q14 deletions. The mechanism needs to be further studied. RARhoGAP contains a PH domain, a Ras-associating domain, a Rho-GAP domain, and ANXL repeats. 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 1831513559 418 RVLIRQSEVMKQTRKELQPRYLVLFTDYLWICRVSSSGQFDINrsYRIPLEYMkfeRMEEDERIRCLQIRSRVKSALI-- 495
Cdd:cd13319     1 RTFLLEGPVQLTRGLQTQERHLFLFSDVLVVAKPKSKNSFKLK--HKIRLSEL---WLASCVDEVCEGSKSADKSFVLgw 75

                          90
                  ....*....|....*...
gi 1831513559 496 -------IFSSEKERNQW 506
Cdd:cd13319    76 pttnfvaTFSSQEEKDLW 93

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513559 420 LIRQSEVMKQT---RKELQPRYLVLFTDYLWICRVSSSGQFDINRSYrIPL---EYMKFERMEEDERIRCLQIR----SR 489
Cdd:pfam00169   1 VVKEGWLLKKGggkKKSWKKRYFVLFDGSLLYYKDDKSGKSKEPKGS-ISLsgcEVVEVVASDSPKRKFCFELRtgerTG 79

                          90       100
                  ....*....|....*....|....*.
gi 1831513559 490 VKSALIIFSSEKERNQWTDDLTKAQY 515
Cdd:pfam00169  80 KRTYLLQAESEEERKDWIKAIQSAIR 105

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831513559 430 TRKELQPRYLVLFTDYLWICRVSSSGQFDINRSYRIPLEYMKfERMEEDERIRCLQIRSRVKSALII-FSSEKERNQWTD 508
Cdd:cd00821    12 GLKSWKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGILEV-EEVSPKERPHCFELVTPDGRTYYLqADSEEERQEWLK 90

                  ..
gi 1831513559 509 DL 510
Cdd:cd00821    91 AL 92