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 1820722095 151 PWIPDKATDICMRCTQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSPKPLRVCSLCYRQL 214
Cdd:cd15754     1 PWIPDKATDICMRCTQTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLSPKPVRVCSLCYRKL 64

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 1820722095 151 PWIPDKATDICMRCTQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSPKPLRVCSLCYRQL 214
Cdd:cd15754     1 PWIPDKATDICMRCTQTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLSPKPVRVCSLCYRKL 64

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 1820722095  149 AAPWIPDKATDICMRCtQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSP-KPLRVCSLCY 211
Cdd:smart00064   1 RPHWIPDEEVSNCMGC-GKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIeRPVRVCDDCY 63

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820722095  42 EGILTKEC---RKKPKPRVFFLFNDILVYGSIVINKRKYNSQHIIPLEDVTLETLPDTLQMKNRWMIK------TSKKSF 112
Cdd:pfam00169   4 EGWLLKKGggkKKSWKKRYFVLFDGSLLYYKDDKSGKSKEPKGSISLSGCEVVEVVASDSPKRKFCFElrtgerTGKRTY 83

                          90       100
                  ....*....|....*....|..
gi 1820722095 113 VVSAASLTERKEWLSHLEECIR 134
Cdd:pfam00169  84 LLQAESEEERKDWIKAIQSAIR 105

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 1820722095 151 PWIPDKATDICMRCTQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSPKPLRVCSLCYRQL 214
Cdd:cd15754     1 PWIPDKATDICMRCTQTNFSLLTRRHHCRKCGFVVCHECSRQRFLIPRLSPKPVRVCSLCYRKL 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 1820722095 152 WIPDKATDICMRCTQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSPKPLRVCSLCYRQL 214
Cdd:cd15755     2 WVPDSEATVCMRCQKAKFTPVNRRHHCRKCGFVVCGPCSEKKFLLPSQSSKPVRVCDFCYDLL 64

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 1820722095  36 GRVLLGEGILTKECRKKPKPRVFFLFNDILVYGSIVINKRKYNSQHIIPLEDVTLEtLPDTLQMKNRWMIKTSKKSFVVS 115
Cdd:cd13389    11 GRKLIKEGELMKVSRKEMQPRYFFLFNDCLLYTTPVQSSGMLKLNNELPLSGMKVK-LPEDEEYSNEFQIISTKRSFTLI 89

                          90
                  ....*....|....*....
gi 1820722095 116 AASLTERKEWLSHLEECIR 134
Cdd:cd13389    90 ASSEEERDEWVKALSRAIE 108

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 1820722095  149 AAPWIPDKATDICMRCtQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSP-KPLRVCSLCY 211
Cdd:smart00064   1 RPHWIPDEEVSNCMGC-GKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIeRPVRVCDDCY 63

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 1820722095 152 WIPDKATDICMRCTQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSPKPLRVCSLCY 211
Cdd:cd15724     1 WVPDEAVSVCMVCQVERFSMFNRRHHCRRCGRVVCSSCSTKKMLVEGYRENPVRVCDQCY 60

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 1820722095 151 PWIPDKATDICMRCtQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRlSPKPLRVCSLCYRQL 214
Cdd:cd15730     2 KWADDEEVQNCMAC-GKGFSVTVRKHHCRQCGNIFCNECSSKTATTPS-SKKPVRVCDACFDDL 63

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1820722095 161 CMRCtQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRL-SPKPLRVCSLCY 211
Cdd:cd00065     2 CMLC-GKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSFgSGKPVRVCDSCY 52

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 1820722095  32 LAVSGRVLLGEGILTKECRKKPKPRVFFLFNDILVYGSIVI---NKRKYNSQhiIPLEDVTLETLPDTLQMKNRWMIKTS 108
Cdd:cd01220     1 LVQPGREFIREGCLQKLSKKGLQQRMFFLFSDVLLYTSRSPtpsLQFKVHGQ--LPLRGLMVEESEPEWGVAHCFTIYGG 78

                          90       100
                  ....*....|....*....|....*.
gi 1820722095 109 KKSFVVSAASLTERKEWLSHLEECIR 134
Cdd:cd01220    79 NRALTVAASSEEEKERWLEDLQRAID 104

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 1820722095 159 DICMRCtQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLS-PKPLRVCSLCYRQL 214
Cdd:cd15720     6 DECHRC-RVQFGVFQRKHHCRACGQVFCGKCSSKSSTIPKFGiEKEVRVCDPCYEKL 61

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1820722095 152 WIPDKATDICMRCtQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRL-SPKPLRVCSLCYRQL 214
Cdd:cd15719     3 WVKDEGGDSCTGC-SVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRLrISRPVRVCQACYNIL 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 1820722095   42 EGILTK---ECRKKPKPRVFFLFNDILVYGSIVINKRKYNSQHIIPLEDVTLETLPDTLQMKNRWMIK---TSKKSFVVS 115
Cdd:smart00233   4 EGWLYKksgGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTVREAPDPDSSKKPHCFEiktSDRKTLLLQ 83

                           90
                   ....*....|....*....
gi 1820722095  116 AASLTERKEWLSHLEECIR 134
Cdd:smart00233  84 AESEEEREKWVEALRKAIA 102

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1820722095 151 PWIPDKATDICmrctQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSPK--PLRVCSLCY 211
Cdd:cd15760     1 HWKPDSRCDVC----RKKFGLFKRRHHCRNCGDSFCSEHSSRRIPLPHLGPLgvPQRVCDRCF 59

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1820722095 159 DICMRCTqTKFSTLTRRHHCRKCGFVVCGDCSRQrfLMPRLS---PKPLRVCSLCYRQL 214
Cdd:cd15728     8 DYCYECG-VKFGITTRKHHCRHCGRLLCSKCSTK--EVPIIKfdlNKPVRVCDVCFDVL 63

Exocyst complex 84-kDa subunit Ral-binding domain/Pleckstrin Homology (PH) domain; The Sec6/8 complex, also called the exocyst complex, forms an octameric protein (Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84) involved in the tethering of secretory vesicles to specific regions on the plasma membrane. The regulation of Sec6/8 complex differs between mammals and yeast. Mamalian Exo84 and Sec5 are effector targets for active Ral GTPases which are not present in yeast. Ral GTPases are members of the Ras superfamily, and as such cycle between an active GTP-bound state and an inactive GDP-bound state. The Exo84 Ral-binding domain adopts a PH domain fold. Mammalian Exo84 and Sec5 competitively bind to active RalA. 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 1820722095  34 VSGRVLLGEGILTKE--CRKKPKPRV-FFLFNDILVYGSIVINKR---KYNSQHIIPLEDVTLETLPDTLQMKNRWMIKT 107
Cdd:cd01226     3 VPGRYLLHEGDLLELdpDDYKPIQKVhLFLLNDVLLIASWLPNRRgpvRYKFQALYPLEDLAVVNVKDLGPVKNAFKLLT 82

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1820722095 108 SKKSFVVSAASLTERKEWLSHLEECIRHLLTK 139
Cdd:cd01226    83 FPETRVFQCENAKIKKEWLEKFEQAKRAKLAK 114

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
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1820722095 160 ICMRCTqTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSPKPLRVCSLCYRQL 214
Cdd:cd15742    11 MCMNCG-SDFTLTLRRHHCHACGKIVCRNCSRNKYPLKYLKDRPAKVCDGCFAEL 64

FYVE-related domain found in RUN and FYVE domain-containing protein 3 (RUFY3) and similar proteins; RUFY3, also termed Rap2-interacting protein x (RIPx or RPIPx), or single axon-regulated protein (singar), is an N-terminal RUN domain and a C-terminal FYVE domain containing protein predominantly expressed in the brain. It suppresses formation of surplus axons for neuronal polarity. Unlike other RUFY proteins, RUFY3 can associate with the GTP-bound active form of Rab5. Moreover, the FYVE domain of RUFY3 resembles the FYVE-related domain as it lacks the WxxD motif (x for any residue).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1820722095 160 ICMRCTQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSPKPLRVCSLCY 211
Cdd:cd15744     1 SCSLCQEDFASLALPKHNCYNCGGTFCDACSSNELPLPSSIYEPARVCDVCY 52

FYVE domain found in WD40 repeat and FYVE domain-containing protein WDFY1 and WDFY2, and similar proteins; This family includes WD40 repeat and FYVE domain-containing protein WDFY1 and WDFY2. WDFY1, also termed FYVE domain containing protein localized to endosomes-1 (FENS-1), or phosphoinositide-binding protein 1, or zinc finger FYVE domain-containing protein 17, is a novel single FYVE domain containing protein that binds phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) with high specificity over other phosphoinositides. WDFY1 to early endosomes requires an intact FYVE domain and is inhibited by wortmannin, a PI3-kinase inhibitor. WDFY2, also termed zinc finger FYVE domain-containing protein 22, or ProF (propeller-FYVE protein), is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein that is localized to a distinct subset of early endosomes close to the plasma membrane. It interacts preferentially with endogenous serine/threonine kinase Akt2, but not Akt1, and plays a specific role in modulating signaling through Akt downstream of the interaction of this kinase with the endosomal proteins APPL (adaptor protein containing PH domain, PTB domain, and leucine zipper motif). In addition to Akt, WDFY2 serves as a binding partner for protein kinase C, zeta (PRKCZ), and its substrate vesicle-associated membrane protein 2 (VAMP2), and is involved in vesicle cycling in various secretory pathways. Moreover, Silencing of WDFY2 by siRNA produces a strong inhibition of endocytosis. Both WDFY1 and WDFY2 contain a FYVE domain and multiple WD-40 repeats.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1820722095 158 TDICMRCTQTKF---------STL-TRRHHCRKCGFVVCGDCSRQRFLMPRLS-PKPLRVCSLCY 211
Cdd:cd15718     6 SDNCQKCSRPFFwnfkqmwekKTLgVRQHHCRKCGKAVCDKCSSNRSTIPVMGfEFPVRVCNECY 70

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820722095  42 EGILTKEC---RKKPKPRVFFLFNDILVYGSIVINKRKYNSQHIIPLEDVTLETLPDTLQMKNRWMIK------TSKKSF 112
Cdd:pfam00169   4 EGWLLKKGggkKKSWKKRYFVLFDGSLLYYKDDKSGKSKEPKGSISLSGCEVVEVVASDSPKRKFCFElrtgerTGKRTY 83

                          90       100
                  ....*....|....*....|..
gi 1820722095 113 VVSAASLTERKEWLSHLEECIR 134
Cdd:pfam00169  84 LLQAESEEERKDWIKAIQSAIR 105

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1820722095 152 WIPDKATDICMRCtQTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRlSPKPLRVCSLCYRQLM 215
Cdd:cd15759     4 WLKDKEATHCKLC-EKEFSLSKRKHHCRNCGEIFCNACSDNELPLPS-SPKPVRVCDSCHAMLI 65

FYVE domain found in WD40 repeat and FYVE domain-containing protein 1 (WDFY1) and similar proteins; WDFY1, also termed FYVE domain containing protein localized to endosomes-1 (FENS-1), or phosphoinositide-binding protein 1, or zinc finger FYVE domain-containing protein 17, is a novel single FYVE domain containing protein that binds phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) with high specificity over other phosphoinositides. WDFY1 to early endosomes requires an intact FYVE domain and is inhibited by wortmannin, a PI3-kinase inhibitor. In addition to FYVE domain, WDFY1 harbors multiple WD-40 repeats.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1820722095 158 TDICMRCTQTKFSTLT----------RRHHCRKCGFVVCGDCSRQRFLMPRLSPK-PLRVCSLCYRQLMAE 217
Cdd:cd15756     6 SDSCQKCEQPFFWNIKqmwdtktlglRQHHCRKCGQAVCGKCSSKRSSYPIMGFEfQVRVCDSCFETIKDE 76

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 1820722095  42 EGILTKECRKK--PKPRVFFLFNDILVYG----SIVINKRKYNSQHIIP---LEDVTLETLPDTLQmknrwmIKTSKKSF 112
Cdd:cd13328     2 EGQILKLSAKNgtPQPRYLFLFNDMLLYCvpklSLVGQKFSVRNRLDVAgmkVREPVNENYPHTFK------ISGKERSL 75

                          90
                  ....*....|....
gi 1820722095 113 VVSAASLTERKEWL 126
Cdd:cd13328    76 ELQASSAEEKDEWI 89

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 1820722095 152 WIPDKATDICMRCtQTKFSTLTRRHHCRKCGFVVCGDCSrQRFLMPRLSPKPLRVCSLCY 211
Cdd:cd15726     1 WQDDTDVTHCLDC-KSEFSWMVRRHHCRLCGRIFCYACS-NFYVLTAHGGKKERCCKACF 58

Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820722095  19 ASVENCFGASGQPLAVSGRVLLGEGILTKECRKKPKPRVFFLFNDILVYGS-IVINKRKYNSQHIIPLEDVTLETLPD-- 95
Cdd:cd01224     9 AWQSTVEGWEGEDLSDRSSELIHSGELTKISAGRAQERTFFLFDHQLVYCKkDLLRRKNYIYKGRIDTDNMEIEDLPDgk 88

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1820722095  96 ------TLqmKNRWMIKTSKKS--FVVSAASLTERKEWLSHLEE 131
Cdd:cd01224    89 ddesgvTV--KNAWKIYNASKNkwYVLCAKSAEEKQRWLEAFAE 130

FYVE domain found in WD40 repeat and FYVE domain-containing protein 2 (WDFY2); WDFY2, also termed zinc finger FYVE domain-containing protein 22, or ProF (propeller-FYVE protein), is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein that is localized to a distinct subset of early endosomes close to the plasma membrane. It interacts preferentially with endogenous serine/threonine kinase Akt2, but not Akt1, and plays a specific role in modulating signaling through Akt downstream of the interaction of this kinase with the endosomal proteins APPL (adaptor protein containing PH domain, PTB domain, and leucine zipper motif). In addition to Akt, WDFY2 serves as a binding partner for protein kinase C, zeta (PRKCZ), and its substrate vesicle-associated membrane protein 2 (VAMP2), and is involved in vesicle cycling in various secretory pathways. Moreover, Silencing of WDFY2 by siRNA produces a strong inhibition of endocytosis. WDFY2 contains WD40 motifs and a FYVE domain.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1820722095 158 TDICMRCTQTKFSTLT----------RRHHCRKCGFVVCGDCSRQRFLMPRLSPK-PLRVCSLCY 211
Cdd:cd15757     6 SDSCQKCDQPFFWNFKqmwdskkiglRQHHCRKCGKAVCGKCSSKRSTIPLMGFEfEVRVCDSCH 70

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 1820722095  37 RVLLGEGILTKECRKKPKPRVFFLFNDILVYGSIViNKRKYNSQHIIPLEDVTLETLPDTLQMKNrwmiKTSKKSF---- 112
Cdd:cd13319     1 RTFLLEGPVQLTRGLQTQERHLFLFSDVLVVAKPK-SKNSFKLKHKIRLSELWLASCVDEVCEGS----KSADKSFvlgw 75

                          90       100
                  ....*....|....*....|..
gi 1820722095 113 -----VVSAASLTERKEWLSHL 129
Cdd:cd13319    76 pttnfVATFSSQEEKDLWLSFL 97

FYVE-related domain found in FYVE domain-containing protein 19 (ZFY19) and similar proteins; ZFY19, also termed mixed lineage leukemia (MLL) partner containing FYVE domain, is encoded by a novel gene, MLL partner containing FYVE domain (MPFYVE). The FYVE domain of ZFY19 resembles FYVE-related domains that are structurally similar to the canonical FYVE domains but lack the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif. The biological function of ZFY19 remains unclear.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1820722095 161 CMRCTqTKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPRLSPKPLRVCSLCY 211
Cdd:cd15749     2 CFGCA-AKFSLFKKECGCKNCGRSFCKGCLTFSAVVPRKGNQKQKVCKQCH 51

p63RhoGEF pleckstrin homology (PH) domain, repeat 2; The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric G protein, Galphaq and linking Galphaq-coupled receptors (GPCRs) to the activation of RhoA. The Dbl(DH) and PH domains of p63RhoGEF interact with the effector-binding site and the C-terminal region of Galphaq and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of Galphaq effectors that appear to activate RhoA both in vitro and in intact cells. Dbs is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Trio is a multidomain signaling protein that contains two RhoGEF(DH)-PH domains in tandem. 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 1820722095  50 RKKPKPRVFFLFNDILVYGSIVINKRKYNS-----QHIIPLEDVTLETL----PDTLQMKNRWMIKTSKkSFVVSAASLT 120
Cdd:cd13241    33 LQKGKERRVFLFEQIIIFSEILGKKTQFSNpgyiyKNHIKVNKMSLEENvdgdPLRFALKSRDPNNPSE-TFILQAASPE 111

                          90
                  ....*....|.
gi 1820722095 121 ERKEWLSHLEE 131
Cdd:cd13241   112 VRQEWVDTINQ 122

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 1820722095 160 ICMRCTQtKFSTLTRRHHCRKCGFVVCGDCSRQRFLMPR-----LSPKPLRVCSLCY 211
Cdd:cd15736     1 CCHTCSR-TFNLNIRAHHCRKCGKLFCRRHLPNMIPLNLsaydpRNGKWYRCCHSCF 56

Ephexin Pleckstrin homology (PH) domain; Ephexin-1 (also called NGEF/ neuronal guanine nucleotide exchange factor) plays a role in the homeostatic modulation of presynaptic neurotransmitter release. Specific functions are still unknown for Ephexin-2 (also called RhoGEF19) and Ephexin-3 (also called Rho guanine nucleotide exchange factor 5/RhoGEF5, Transforming immortalized mammary oncogene/p60 TIM, and NGEF/neuronalGEF). Ephexin-4 (also called RhoGEF16) acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. This in turn results in the activation of RhoG which recruits ELMO2 and Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells. Ephexin-5 is the specific GEF for RhoA activation and the regulation of vascular smooth muscle contractility. It interacts with EPHA4 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. The members of the Ephexin family contains a RhoGEF (DH) followed by a PH domain and an SH3 domain. The ephexin PH domain is believed to act with the DH domain in mediating protein-protein interactions. 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 1820722095  31 PLAVSGRVLLGEGILTKEC----------RKKPKPRVFFLFNDILvygsiVINKRKYNSQHII----PLEDVTLETLPDT 96
Cdd:cd01221     6 PLISSSRWLVKRGELTELVedggsltfrkKFSKTPVYLFLFNDLL-----LITKKKSEERYLVldyaPRNLVQVEEVEDP 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1820722095  97 LQ-----MKNRWMIKTS------KKSFVVSAASLTERKEWLS 127
Cdd:cd01221    81 LQlpqplGKNLFLLTLLenhegkTVELLLSAESESDRERWLS 122