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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 71984671  532 GKTSPYWIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEegkklQAVRVCKPCSAML 604
Cdd:cd15729    1 GKVAPVWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEYLDN-----KEARVCVPCYQTL 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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 71984671  532 GKTSPYWIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEegkklQAVRVCKPCSAML 604
Cdd:cd15729    1 GKVAPVWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEYLDN-----KEARVCVPCYQTL 68

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 71984671    536 PYWIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEEGKKlqaVRVCKPC 600
Cdd:pfam01363    1 PVWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISLLPELGSNKP---VRVCDAC 62

hypothetical protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984671   511 DSDESATPRRERRLTESELQLGKTSPYWIPDSECPNCMLCNTRFTIIT-------------------RRHHCRACGRVLC 571
Cdd:PHA02893    1 DAASTAGAKKRKKKSRSATSTRKEEETAIPEDACTTCQICQSKLVMFSgvnkyklkdylnigkafsnSNIKCIACGSSLC 80

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 71984671  532 GKTSPYWIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEegkklQAVRVCKPCSAML 604
Cdd:cd15729    1 GKVAPVWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACCSLKARLEYLDN-----KEARVCVPCYQTL 68

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 71984671    536 PYWIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEEGKKlqaVRVCKPC 600
Cdd:pfam01363    1 PVWVPDSSATVCMICSKPFTFFRRRHHCRNCGRVFCSACSSKKISLLPELGSNKP---VRVCDAC 62

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 71984671  536 PYWIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLqeegkKLQAVRVCKPC 600
Cdd:cd15743    1 PIWIPDSRVTMCMICTSEFTVTWRRHHCRACGKVVCGSCSSNKAPLEYL-----KNKSARVCDEC 60

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 71984671  546 NCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEEGKklqaVRVCKPC 600
Cdd:cd00065    1 RCMLCGKKFSLFRRRHHCRRCGRVFCSKCSSKKLPLPSFGSGKP----VRVCDSC 51

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 71984671  537 YWIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEEGKklqaVRVCKPC 600
Cdd:cd15725    1 YWMPDSSCKECYECSEKFTTFRRRHHCRLCGQIFCSRCCNQEIPGKFIGYPGD----LRVCTYC 60

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 71984671  538 WIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLeylqEEGKKLQAVRVCKPC 600
Cdd:cd15733    1 WVPDHAASHCFGCDCEFWLAKRKHHCRNCGNVFCADCSNYKLPI----PDEQLYDPVRVCNSC 59

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 71984671  538 WIPDSECPNCMLC-NTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEegkklQAVRVCKPC 600
Cdd:cd15724    1 WVPDEAVSVCMVCqVERFSMFNRRHHCRRCGRVVCSSCSTKKMLVEGYRE-----NPVRVCDQC 59

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 71984671  538 WIPDSECpncMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAfleYLQEEGKKLQAVRVCKPC 600
Cdd:cd15760    2 WKPDSRC---DVCRKKFGLFKRRHHCRNCGDSFCSEHSSRRI---PLPHLGPLGVPQRVCDRC 58

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 71984671  538 WIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGS----CCNE--------------KAFLEYLQEEGKKLQAVRVCKP 599
Cdd:cd15737    2 WEDDSSVTHCPICLRSFGLLLRKHHCRLCGKVVCDDrrtkCSTEvpldllssalpdlpFVFKEPQSDIPDDTKSVRVCRD 81

                 .
gi 71984671  600 C 600
Cdd:cd15737   82 C 82

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 71984671  539 IPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSC-CNEKAFLEYlqeegKKLQAVRVCKPCSAML 604
Cdd:cd15728    2 PPWADGDYCYECGVKFGITTRKHHCRHCGRLLCSKCsTKEVPIIKF-----DLNKPVRVCDVCFDVL 63

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 71984671  538 WIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNekaFLEYLQEEGKKlqaVRVCKPCS 601
Cdd:cd15726    1 WQDDTDVTHCLDCKSEFSWMVRRHHCRLCGRIFCYACSN---FYVLTAHGGKK---ERCCKACF 58

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 71984671  542 SECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEEGKklqaVRVCKPC 600
Cdd:cd15720    3 KDGDECHRCRVQFGVFQRKHHCRACGQVFCGKCSSKSSTIPKFGIEKE----VRVCDPC 57

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 71984671  536 PYWipdSECPNCMLCNTRF-----------TIITRRHHCRACGRVLCGSCCNEKAFLEYLQEEgkklQAVRVCKPC 600
Cdd:cd15718    1 PEW---AESDNCQKCSRPFfwnfkqmwekkTLGVRQHHCRKCGKAVCDKCSSNRSTIPVMGFE----FPVRVCNEC 69

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 71984671  537 YWIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLqeegKKLQAVRVCKPCSAML 604
Cdd:cd15719    2 HWVKDEGGDSCTGCSVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRL----RISRPVRVCQACYNIL 65

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        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 71984671  538 WIPDSECPNCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAfleYLQEEGKklqAVRVCKPC 600
Cdd:cd15721    1 WADDKEVTHCQQCEKEFSLSRRKHHCRNCGGIFCNSCSDNTM---PLPSSAK---PVRVCDTC 57

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 71984671  547 CMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEYLQEEGKklqaVRVCKPCS 601
Cdd:cd15745    2 CAICAKAFSLFRRKYVCRLCGGVVCHSCSSEDLVLSVPDTCIY----LRVCKTCY 52

FYVE-related domain found in protrudin and similar proteins; Protrudin, also termed zinc finger FYVE domain-containing protein 27 (ZFY27 or ZFYVE27), is a FYVE domain-containing protein involved in transport of neuronal cargoes and implicated in the onset of hereditary spastic paraplegia (HSP). It is involved in neurite outgrowth through binding to spastin. Moreover, it functions as a key regulator of the Rab11-dependent membrane trafficking during neurite extension. It serves as an adaptor molecule that links its associated proteins, such as Rab11-GDP, VAP-A and -B, Surf4, and RTN3, to KIF5, a motor protein that mediates anterograde vesicular transport in neurons, and thus plays a key role in the maintenance of neuronal function. The FYVE domain of protrudin resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks 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. In addition, unlike canonical FYVE domains that is located to early endosomes and specifically binds to phosphatidylinositol 3-phosphate (PtdIns3P or PI3P), the FYVE domain of protrudin is located to plasma membrane and preferentially binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). In addition to FYVE-related domain, protrudin also contains a Rab11-binding domain (RBD11), two hydrophobic domains, HP-1 and HP-2, an FFAT motif, and a coiled-coil domain.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 71984671  546 NCMLCNTRFTIIT-RRHHCRACGRVLCGSCCNEKAFLEYLQEEGK--KLQAVRVCKPCSAML 604
Cdd:cd15723    1 NCTGCGASFSVLLkKRRSCNNCGNAFCSRCCSKKVPRSVMGATAPaaQRETVFVCSGCNDKL 62

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 71984671  536 PYWIPDSECPNC---------MLCNTRfTIITRRHHCRACGRVLCGSCCNEKAFLEYLqeeGKKLQaVRVCKPC 600
Cdd:cd15756    1 PQWLESDSCQKCeqpffwnikQMWDTK-TLGLRQHHCRKCGQAVCGKCSSKRSSYPIM---GFEFQ-VRVCDSC 69

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 71984671  546 NCMLCNTRFTIITRRHHCRACGRVLCGSCCNEKAFLEylqEEGKKLQavRVCKPC 600
Cdd:cd15749    1 RCFGCAAKFSLFKKECGCKNCGRSFCKGCLTFSAVVP---RKGNQKQ--KVCKQC 50

Ring-infected erythrocyte surface antigen; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984671   334 NLQNEK-IDVEFIENSEAIVQNESEDVPESNSTSGTVLENIEDHLESDVVIENGSESS----FVNEKMNEASTAHLVAEQ 408
Cdd:PTZ00341  418 DLEKQKyMDMLDGSEDESVEDNEEEHSGDANEEELSVDEHVEEHNADDSGEQQSDDESgehqSVNEIVEEQSVNEHVEEP 497

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 71984671   409 SVVDDSEihLETEDQETLSPETADSSTNKNSDEFPDEGSQSEASVnNEEVLENVEHVEDECTVVDAVNE 477
Cdd:PTZ00341  498 TVADIVE--QETVDEHVEEPAVDENEEQQTADEHVEEPTIAEEHV-EEEISTAEEHIEEPASDVQQDSE 563

Ring-infected erythrocyte surface antigen; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984671   288 LNSFNADNHNylsepENSSKKERMQSVAEEN--EASEEPTQSSSE--TEKNLQnEKIDVEFIENSEAIVQNESEDVPESN 363
Cdd:PTZ00341  921 INLINKELKN-----QNENVPEHLKEHAEANieEDAEENVEEDAEenVEENVE-ENVEENVEENVEENVEENVEENVEEN 994

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984671   364 stsgtVLENIEDHLESDVViENGSESSFVNEKMNEASTAHLVAEQSVVDDSEIHLETEDQetlSPETADSSTNKNSDEFP 443
Cdd:PTZ00341  995 -----VEENVEENIEENVE-ENVEENIEENVEEYDEENVEEVEENVEEYDEENVEEIEEN---AEENVEENIEENIEEYD 1065

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*.
gi 71984671   444 DEGSQSEASVNNEEVLENVE-HVEDECTVVDA-VNENTDSSIEEND 487
Cdd:PTZ00341 1066 EENVEEIEENIEENIEENVEeNVEENVEEIEEnVEENVEENAEENA 1111

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        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 71984671  545 PNCMLCNTRFTIITRRHHCRACGRVLCGSCcnekafleYLQEEGKklqaVRVCKPCSA 602
Cdd:cd15750    1 MPCESCGAKFSVFKRKRTCADCKRYFCSNC--------LSKEERG----RRRCRRCRA 46

FYVE-related domain found in Slp homolog lacking C2 domains c (SlaC2-c) and similar proteins; SlaC2-c, also termed Rab effector MyRIP, or exophilin-8, or myosin-VIIa- and Rab-interacting protein, or synaptotagmin-like protein lacking C2 domains c, is a GTP-bound form of Rab27A-, myosin Va/VIIa-, and actin-binding protein mainly present on retinal melanosomes and secretory granules. It may play a role in insulin granule exocytosis. It is also involved in the control of isoproterenol (IPR)-induced amylase release from parotid acinar cells. SlaC2-c belongs to the Slp homolog lacking C2 domains (Slac2) family. It contains an N-terminal Slp homology domain (SHD), but lacks tandem C2 domains. The SHD consists of two conserved regions, designated SHD1 (Slp homology domain 1) and SHD2, which may function as protein interaction sites. The SHD1 and SHD2 of SlaC2-c are separated by a putative FYVE zinc finger, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks 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. Moreover, Slac2-c has a middle myosin-binding domain and a C-terminal actin-binding domain.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 71984671  547 CMLCNTRFTII-TRRHHCRACGRVLCGSCCnekaflEYLQEEgkKLQAVRVC 597
Cdd:cd15753    2 CMRCCSPFTFLfNRKRQCRDCKFNVCKSCA------SYDKKE--KGWTCNVC 45

FYVE-related domain found in Spir proteins, Spire1 and Spire2; Spir proteins were originally discovered as the protein products of the Drosophila spire gene. They are Jun N-terminal kinase (JNK)-interacting proteins that have exclusively been identified in metazoans. They may play roles in membrane trafficking and cortical filament crosslinking. This family includes Spire1 and Spire2, which function as new essential factors in asymmetric division of oocytes. They mediate asymmetric spindle positioning by assembling a cytoplasmic actin network. They are also required for polar body extrusion by promoting assembly of the cleavage furrow. Moreover, they cooperate synergistically with Fmn2 to assemble F-actin in oocytes. Both Spire1 and Spire2 contain an N-terminal protein-interaction KIND domain, WH2 actin-binding domains, a Rab GTPase-interaction Spir-box, and a C-terminal FYVE membrane-binding domain. Their FYVE domains resemble 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, which form a binding pocket that specifically bind the phospholipid phosphatidylinositol 3-phosphate (PtdIns3P or PI3P).

                         10        20        30
                 ....*....|....*....|....*....|
gi 71984671  547 CMLC-NTRFTIITRRHHCRACGRVLCGSCC 575
Cdd:cd15748    5 CFCCkKKKFSFFTWPNTCKLCKRVVCSKCC 34