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 1676319415  738 GQKQPTWVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYLE-KEARVCVVCYETI 804
Cdd:cd15729      1 GKVAPVWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEYLDnKEARVCVPCYQTL 68

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 1676319415  738 GQKQPTWVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYLE-KEARVCVVCYETI 804
Cdd:cd15729      1 GKVAPVWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEYLDnKEARVCVPCYQTL 68

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

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1676319415   742 PTWVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYL--EKEARVCVVCYETISK 806
Cdd:smart00064    2 PHWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLgiERPVRVCDDCYENLNG 68

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 1676319415  738 GQKQPTWVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYLE-KEARVCVVCYETI 804
Cdd:cd15729      1 GKVAPVWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEYLDnKEARVCVPCYQTL 68

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

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1676319415   742 PTWVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYL--EKEARVCVVCYETISK 806
Cdd:smart00064    2 PHWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLgiERPVRVCDDCYENLNG 68

FYVE domain found in protein containing both PH and FYVE domains 1 (phafin-1), 2 (phafin-2), and similar proteins; This family includes protein containing both PH and FYVE domains 1 (phafin-1) and 2 (phafin-2). Phafin-1 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. Phafin-2 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 1676319415  743 TWVPDSEAPNCMNC-QVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYL-EKEARVCVVCY 801
Cdd:cd15717      1 VWVPDSEAPVCMHCkKTKFTAINRRHHCRKCGAVVCGACSSKKFLLPHQsSKPLRVCDTCY 61

FYVE domain found in lateral signaling target protein 2 homolog (Lst2) and similar proteins; Lst2, also termed zinc finger FYVE domain-containing protein 28, is a monoubiquitinylated phosphoprotein that functions as a negative regulator of epidermal growth factor receptor (EGFR) signaling. Unlike other FYVE domain-containing proteins, Lst2 displays primarily non-endosomal localization. Its endosomal localization is regulated by monoubiquitinylation. Lst2 physically binds Trim3, also known as BERP or RNF22, which is a coordinator of endosomal trafficking and interacts with Hrs and a complex that biases cargo recycling.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1676319415  742 PTWVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYL--EKEARVCVVCY 801
Cdd:cd15731      3 PLWVPDEACPQCMACSAPFTVLRRRHHCRNCGKIFCSRCSSNSVPLPRYgqMKPVRVCNHCF 64

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 1676319415  752 NCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYL--EKEARVCVVCY 801
Cdd:cd00065      1 RCMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSFgsGKPVRVCDSCY 52

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 1676319415  742 PTWVPDSEAPNCMNCQVKFTF-TKRRHHCRACGKVFCGVCCNRKCKLQY-LEKEARVCVVCY 801
Cdd:cd15741      1 PRWVRDNEVTMCMRCKEPFNAlTRRRHHCRACGYVVCWKCSDYKATLEYdGNKLNRVCKHCY 62

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 1676319415  748 SEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKL-QY-LEKEARVCVVCYETI 804
Cdd:cd15720      3 KDGDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSKSSTIpKFgIEKEVRVCDPCYEKL 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 1676319415  744 WVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYLEK--EARVCVVCYE 802
Cdd:cd15725      2 WMPDSSCKECYECSEKFTTFRRRHHCRLCGQIFCSRCCNQEIPGKFIGYpgDLRVCTYCCK 62

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 1676319415  744 WVPDSEapnCMNCQVKFTFTKRRHHCRACGKVFCGV-CCNRKCKLQYLEK--EARVCVVCY 801
Cdd:cd15760      2 WKPDSR---CDVCRKKFGLFKRRHHCRNCGDSFCSEhSSRRIPLPHLGPLgvPQRVCDRCF 59

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1676319415  743 TWVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCgvccnRKCKlQYLEKEARVCVVCYETISK 806
Cdd:cd15716      3 PWVNDSDVPFCPDCGKKFNLARRRHHCRLCGSIMC-----NKCS-QFLPLHIRCCHHCKDLLER 60

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
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1676319415  744 WVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYLEKEARVCVVCY 801
Cdd:cd15726      1 WQDDTDVTHCLDCKSEFSWMVRRHHCRLCGRIFCYACSNFYVLTAHGGKKERCCKACF 58

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 1676319415  740 KQPTWVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYLEKEARVCVVCY 801
Cdd:cd15758      2 KGHAWLKDDEATHCKQCEKEFSISRRKHHCRNCGHIFCNTCSSNELALPSYPKPVRVCDSCH 63

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        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1676319415  741 QPTWvpdSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVC-CNRKCKLQY-LEKEARVCVVCYE 802
Cdd:cd15728      1 EPPW---ADGDYCYECGVKFGITTRKHHCRHCGRLLCSKCsTKEVPIIKFdLNKPVRVCDVCFD 61

FYVE domain 2 found in yeast protein VAC1 (Vac1p) and similar proteins; 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 family corresponds to the second FYVE domain that is responsible for the ability of Pep7p to efficiently interact with Vac1p and Vps45p.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676319415  744 WVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVcCNRKC--------------KLQYLEKEA-----------RVCV 798
Cdd:cd15737      2 WEDDSSVTHCPICLRSFGLLLRKHHCRLCGKVVCDD-RRTKCstevpldllssalpDLPFVFKEPqsdipddtksvRVCR 80

                   ..
gi 1676319415  799 VC 800
Cdd:cd15737     81 DC 82

FYVE domain found in uncharacterized rab GTPase-binding effector proteins from bilateria; This family includes a group of uncharacterized rab GTPase-binding effector proteins found in bilateria. Although their biological functions remain unclear, they all contain a FYVE domain that harbors a putative phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding site.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1676319415  744 WVPDSEAPNCMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQYLEKEARVCVVCYETISKAQA 809
Cdd:cd15739      4 WQHEDDVDQCPNCKTPFSVGKRKHHCRHCGKIFCSDCLTKTVPSGPNRRPARVCDVCHTLLVKDSA 69

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        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1676319415  742 PTWvpdSEAPNCMNCQVKF-----------TFTKRRHHCRACGKVFCGVCCNRKCKLQYL--EKEARVCVVCY 801
Cdd:cd15718      1 PEW---AESDNCQKCSRPFfwnfkqmwekkTLGVRQHHCRKCGKAVCDKCSSNRSTIPVMgfEFPVRVCNECY 70

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 1676319415  742 PTWVpdsEAPNCMNCQVKF-----------TFTKRRHHCRACGKVFCGVCCNRKCKLQYL--EKEARVCVVCYETI 804
Cdd:cd15756      1 PQWL---ESDSCQKCEQPFfwnikqmwdtkTLGLRQHHCRKCGQAVCGKCSSKRSSYPIMgfEFQVRVCDSCFETI 73

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 1676319415  747 DSEAPNCMNCQVKFTF-TKRRHHCRACGKVFCGVCCNRKcklQYLEKEARVCVVCY 801
Cdd:cd15740      2 EKEKQTCKGCNESFNSiTKRRHHCKQCGAVICGKCSEFK---DLASRHNRVCRDCF 54

FYVE-related domain found in RUN and FYVE domain-containing protein 4 (RUFY4) and similar proteins; RUFY4 belongs to the FUFY protein family which is characterized by the presence of an N-terminal RUN domain and a C-terminal FYVE domain. The FYVE domain of RUFY4 resembles the FYVE-related domain as it lacks the WxxD motif (x for any residue). The biological function of RUFY4 still remains unclear.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1676319415  753 CMNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKLQ--YLEKEARVCVVCY 801
Cdd:cd15745      2 CAICAKAFSLFRRKYVCRLCGGVVCHSCSSEDLVLSvpDTCIYLRVCKTCY 52

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        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676319415  744 WVPDSEAPNCmNCQVKFTFTKRRHHCRACGKVFCGVCCNRKCKL--QYLEKEARVCVVCY 801
Cdd:cd15738      3 WKSFRNVTEC-SCSTPFDHFSKKHHCWRCGNVFCTRCIDKQRALpgHLSQRPVPVCRACY 61

FYVE-like domain found in caspase-associated ring proteins, CARP1 and CARP2; CARP1 and CARP2 are a novel group of caspase regulators by the presence of a FYVE-type zinc finger domain. 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 (x for any residue) motif that is conserved only in phosphoinositide binding FYVE domains. Thus they constitute a family of unique FYVE-type domains called FYVE-like domains.

                           10        20        30
                   ....*....|....*....|....*....|
gi 1676319415  751 PNCMNCQVKFTFTKRRHHCRACGKVFCGVC 780
Cdd:cd15750      1 MPCESCGAKFSVFKRKRTCADCKRYFCSNC 30

phosphatidylinositol kinase; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676319415  714 GGSSFVTANEDSVPE----NTCkeGLVLGQKQPTWVPDSEAPN-CMNCQVKFT-----FTKRRHHCRACGKVFCGVCCNR 783
Cdd:PTZ00303   421 GGSAAARATVGGVAEenelNTF--GLTKLLHNPSWQKDDESSDsCPSCGRAFIslsrpLGTRAHHCRSCGIRLCVFCITK 498

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 1676319415  784 KCKLQYL---------EKEAR-VCVVC---YETISK 806
Cdd:PTZ00303   499 RAHYSFAklakpgssdEAEERlVCDTCykeYETVSQ 534