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 1907101490 213 PEWLDSDSCQKCDQPFFWNFKQMWDSKKIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15718     1 PEWAESDNCQKCSRPFFWNFKQMWEKKTLGVRQHHCRKCGKAVCDKCSSNRSTIPVMGFEFPVRVCNECY 70

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 1907101490 213 PEWLDSDSCQKCDQPFFWNFKQMWDSKKIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15718     1 PEWAESDNCQKCSRPFFWNFKQMWEKKTLGVRQHHCRKCGKAVCDKCSSNRSTIPVMGFEFPVRVCNECY 70

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490   6 SCMSFNPETRRLSIGLDNGTISEFilseDYNKMTPVKNYQAHQSRVTMVLFVLELEWVLSTGQDKQFA-WHcSESGQRLG 84
Cdd:COG2319   208 RSVAFSPDGKLLASGSADGTVRLW----DLATGKLLRTLTGHSGSVRSVAFSPDGRLLASGSADGTVRlWD-LATGELLR 282

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490  85 --GYRTSAVASgLQFDVETRHVFIGDHSGQVTILKLEqeNCTLLTSFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWDI 162
Cdd:COG2319   283 tlTGHSGGVNS-VAFSPDGKLLASGSDDGTVRLWDLA--TGKLLRTLTGHTGAVRSVAFSPDGKTLASGSDDGTVRLWDL 359

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....
gi 1907101490 163 GGRKGTAiELQGHNDKVQALSYAQHTRQLISCGGDGGIVVWNMD 206
Cdd:COG2319   360 ATGELLR-TLTGHTGAVTSVAFSPDGRTLASGSADGTVRLWDLA 402

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1907101490 213 PEWL---DSDSCQKCDQPFFWNFkqmwdskkiglRQHHCRKCGKAVCGKCSSKR-SSIPLMGFEFEVRVCDSCHEAIT 286
Cdd:pfam01363   1 PVWVpdsSATVCMICSKPFTFFR-----------RRHHCRNCGRVFCSACSSKKiSLLPELGSNKPVRVCDACYDTLQ 67

WD domain, G-beta repeat;

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 1907101490 124 TLLTSFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWD 161
Cdd:pfam00400   2 KLLKTLEGHTGSVTSLAFSPDGKLLASGSDDGTVKVWD 39

coronin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490 131 GHTGGVTALCWDPVQ-RVLFSGSSDHSVIMWDI---GGRKGTA---IELQGHNDKVQALSYAQHTRQ-LISCGGDGGIVV 202
Cdd:PTZ00421   73 GQEGPIIDVAFNPFDpQKLFTASEDGTIMGWGIpeeGLTQNISdpiVHLQGHTKKVGIVSFHPSAMNvLASAGADMVVNV 152

                  ....*..
gi 1907101490 203 WnmDVER 209
Cdd:PTZ00421  153 W--DVER 157

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 1907101490 213 PEWLDSDSCQKCDQPFFWNFKQMWDSKKIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15718     1 PEWAESDNCQKCSRPFFWNFKQMWEKKTLGVRQHHCRKCGKAVCDKCSSNRSTIPVMGFEFPVRVCNECY 70

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490 213 PEWLDSDSCQKCDQPFFWNFKQMWDSKKIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15757     1 PEWLDSDSCQKCDQPFFWNFKQMWDSKKIGLRQHHCRKCGKAVCGKCSSKRSTIPLMGFEFEVRVCDSCH 70

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490   6 SCMSFNPETRRLSIGLDNGTISEFilseDYNKMTPVKNYQAHQSRVTMVLFVLELEWVLSTGQDKQFA-WHcSESGQRLG 84
Cdd:COG2319   208 RSVAFSPDGKLLASGSADGTVRLW----DLATGKLLRTLTGHSGSVRSVAFSPDGRLLASGSADGTVRlWD-LATGELLR 282

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490  85 --GYRTSAVASgLQFDVETRHVFIGDHSGQVTILKLEqeNCTLLTSFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWDI 162
Cdd:COG2319   283 tlTGHSGGVNS-VAFSPDGKLLASGSDDGTVRLWDLA--TGKLLRTLTGHTGAVRSVAFSPDGKTLASGSDDGTVRLWDL 359

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....
gi 1907101490 163 GGRKGTAiELQGHNDKVQALSYAQHTRQLISCGGDGGIVVWNMD 206
Cdd:COG2319   360 ATGELLR-TLTGHTGAVTSVAFSPDGRTLASGSADGTVRLWDLA 402

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490  34 DYNKMTPVKNYQAHQSRVTMVLFVLELEWVLSTGQDKQFAWHCSESGQRLGGYR--TSAVASgLQFDVETRHVFIGDHSG 111
Cdd:cd00200    79 DLETGECVRTLTGHTSYVSSVAFSPDGRILSSSSRDKTIKVWDVETGKCLTTLRghTDWVNS-VAFSPDGTFVASSSQDG 157

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490 112 QVTILKLEQENCtlLTSFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWDIggRKGTAI-ELQGHNDKVQALSYAQHTRQ 190
Cdd:cd00200   158 TIKLWDLRTGKC--VATLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLWDL--STGKCLgTLRGHENGVNSVAFSPDGYL 233

                         170
                  ....*....|....*.
gi 1907101490 191 LISCGGDGGIVVWNMD 206
Cdd:cd00200   234 LASGSEDGTIRVWDLR 249

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1907101490 213 PEWL---DSDSCQKCDQPFFWNFkqmwdskkiglRQHHCRKCGKAVCGKCSSKR-SSIPLMGFEFEVRVCDSCHEAIT 286
Cdd:pfam01363   1 PVWVpdsSATVCMICSKPFTFFR-----------RRHHCRNCGRVFCSACSSKKiSLLPELGSNKPVRVCDACYDTLQ 67

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490 125 LLTSFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWDIGGRKGTaIELQGHNDKVQALSYAQHTRQLISCGGDGGIVVWN 204
Cdd:cd00200     1 LRRTLKGHTGGVTCVAFSPDGKLLATGSGDGTIKVWDLETGELL-RTLKGHTGPVRDVAASADGTYLASGSSDKTIRLWD 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490 205 MDVERQ-----------------ETPEWLDSDSCQKCDQpfFWNFKQmwDSKKIGLRQH-----HCR--KCGKAVCGkCS 260
Cdd:cd00200    80 LETGECvrtltghtsyvssvafsPDGRILSSSSRDKTIK--VWDVET--GKCLTTLRGHtdwvnSVAfsPDGTFVAS-SS 154

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1907101490 261 SKRSsiplmgfefeVRVCDscheaiTDEERaPTATFHDSKHNIVHVHFDATRGWLLTSGTDKVIKLWDM 329
Cdd:cd00200   155 QDGT----------IKLWD------LRTGK-CVATLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLWDL 206

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907101490 213 PEWLDSDSCQKCDQPF-FWNfkqmwdskkiglRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15735     1 PEWVDSDVCMRCRTAFtFTN------------RKHHCRNCGGVFCQQCSSKSLPLPHFGINQPVRVCDGCY 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        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907101490 213 PEWLDSDSCQKCDQPFfwnfkqmwdskKIGLRQHHCRKCGKAVCGKCSSKRssIPLMGFEFE--VRVCDSC 281
Cdd:cd15728     2 PPWADGDYCYECGVKF-----------GITTRKHHCRHCGRLLCSKCSTKE--VPIIKFDLNkpVRVCDVC 59

FYVE domain found in zinc finger FYVE domain-containing protein 21 (ZF21) and similar proteins; ZF21 is phosphoinositide-binding protein that functions as a regulator of focal adhesions and cell movement through interaction with focal adhesion kinase. It can also bind to the cytoplasmic tail of membrane type 1 matrix metalloproteinase, a potent invasion-promoting protease, and play a key role in regulating multiple aspects of cancer cell migration and invasion. ZF21 contains a FYVE domain, which corresponds to this model.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1907101490 213 PEWLDSDSCQKCDqpffwNFKQMWDSKKiglRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSC 281
Cdd:cd15727     2 PPWVPDKECPVCM-----SCKKKFDFFK---RRHHCRRCGKCFCSDCCSNKVPLPRMCFVDPVRVCNEC 62

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

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1907101490 243 LRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSC 281
Cdd:cd15734    22 LSKHHCRACGQGVCDDCSKNRRPVPSRGWDHPVRVCDPC 60

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
                  ....*....|....*....|....*....|....*....
gi 1907101490 244 RQHHCRKCGKAVCGKCSSKRSSIPLMGfEFEVRVCDSCH 282
Cdd:cd15717    24 RRHHCRKCGAVVCGACSSKKFLLPHQS-SKPLRVCDTCY 61

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907101490 215 WLDSD---SCQKCDQPFfwnfkqmwdskKIGLRQHHCRKCGKAVCGKCSSKRssIPLMGFEFEVRVCDSCH 282
Cdd:cd15721     1 WADDKevtHCQQCEKEF-----------SLSRRKHHCRNCGGIFCNSCSDNT--MPLPSSAKPVRVCDTCY 58

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490 110 SGQVTILKLEQENCTLLTSFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWDIGGRKGTAIeLQGHNDKVQALSYAQHTR 189
Cdd:COG2319    55 AGDLTLLLLDAAAGALLATLLGHTAAVLSVAFSPDGRLLASASADGTVRLWDLATGLLLRT-LTGHTGAVRSVAFSPDGK 133

                          90
                  ....*....|....*..
gi 1907101490 190 QLISCGGDGGIVVWNMD 206
Cdd:COG2319   134 TLASGSADGTVRLWDLA 150

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
                  ....*....|....*....|....*....|....*....|..
gi 1907101490 244 RQHHCRKCGKAVCGKCSSKRSSIPLMGFEfEVRVCDSCHEAI 285
Cdd:cd15755    24 RRHHCRKCGFVVCGPCSEKKFLLPSQSSK-PVRVCDFCYDLL 64

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 1907101490 219 DSCQKCDQPFfwnfkqmwdskKIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15719    10 DSCTGCSVRF-----------SLTERRHHCRNCGQLFCSKCSRFESEIRRLRISRPVRVCQACY 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
                  ....*....|....*....|....*....|....*...
gi 1907101490 244 RQHHCRKCGKAVCGKCSSKRSSIPLMGFEfEVRVCDSC 281
Cdd:cd15743    24 RRHHCRACGKVVCGSCSSNKAPLEYLKNK-SARVCDEC 60

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 1907101490 218 SDSCQKCDQPFFWNFKqmwdskkiglRQHHCRKCGKAVCGKCSSKRSSIPLMGFEfEVRVCDSCHEAI 285
Cdd:cd15754     8 TDICMRCTQTNFSLLT----------RRHHCRKCGFVVCHECSRQRFLIPRLSPK-PVRVCSLCYRKL 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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907101490 220 SCQKCDQPFFWNFKQmwdskkiglrQHHCRKCGKAVCGKCSSKRSSIPLMGFEfEVRVCDSCH 282
Cdd:cd15744     1 SCSLCQEDFASLALP----------KHNCYNCGGTFCDACSSNELPLPSSIYE-PARVCDVCY 52

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490 215 WLD---SDSCQKCDQPFFwnfkqmwdskkIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSC 281
Cdd:cd15732     2 WVPdhlAASCYGCEREFW-----------LASRKHHCRNCGNVFCGSCCNQKLPVPSQQLFEPSRVCKSC 60

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1907101490 213 PEWLDSDS---CQKCDQPFFWNFKqmwdskkiglRQHHCRKCGKAVCGKCSSKRSSIPLMGfEFEVRVCDSCHEAI 285
Cdd:cd15741     1 PRWVRDNEvtmCMRCKEPFNALTR----------RRHHCRACGYVVCWKCSDYKATLEYDG-NKLNRVCKHCYVIL 65

phosphatidylinositol kinase; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490  213 PEWL----DSDSCQKCDQPFfwnfkqMWDSKKIGLRQHHCRKCGKAVCGKCSSKRS-------SIPLMGFEFEVR-VCDS 280
Cdd:PTZ00303   451 PSWQkddeSSDSCPSCGRAF------ISLSRPLGTRAHHCRSCGIRLCVFCITKRAhysfaklAKPGSSDEAEERlVCDT 524

                   ...
gi 1907101490  281 CHE 283
Cdd:PTZ00303   525 CYK 527

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
                  ....*....|....*....|....*....|....*....|.
gi 1907101490 243 LRQHHCRKCGKAVCGKCSskRSSIPLMGFEFEV-RVCDSCH 282
Cdd:cd15742    23 LRRHHCHACGKIVCRNCS--RNKYPLKYLKDRPaKVCDGCF 61

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490 171 ELQGHNDKVQALSYAQHTRQLISCGGDGGIVVWNMDVERQETpewldsdscqkcdqpffwnfkqmwdskkiGLRQHHcrk 250
Cdd:cd00200     4 TLKGHTGGVTCVAFSPDGKLLATGSGDGTIKVWDLETGELLR-----------------------------TLKGHT--- 51

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907101490 251 cGKAVCGKCSSKRSSIPLMGFEFEVRVCDScheaitdEERAPTATFHDSKHNIVHVHFDATRGWLLTSGTDKVIKLWDMT 330
Cdd:cd00200    52 -GPVRDVAASADGTYLASGSSDKTIRLWDL-------ETGECVRTLTGHTSYVSSVAFSPDGRILSSSSRDKTIKVWDVE 123

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
                  ....*....|....*....|....*....|....*....|....*...
gi 1907101490 244 RQHHCRKCGKAVCGKCSSKRSSIPLMG------FEFEVRVCDSCHEAI 285
Cdd:cd15723    15 KRRSCNNCGNAFCSRCCSKKVPRSVMGatapaaQRETVFVCSGCNDKL 62

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

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1907101490 244 RQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15738    23 KKHHCWRCGNVFCTRCIDKQRALPGHLSQRPVPVCRACY 61

WD40 repeats; Note that these repeats are permuted with respect to the structural repeats (blades) of the beta propeller domain.

                           10        20        30
                   ....*....|....*....|....*....|....
gi 1907101490  171 ELQGHNDKVQALSYAQHTRQLISCGGDGGIVVWN 204
Cdd:smart00320   7 TLKGHTGPVTSVAFSPDGKYLASGSDDGTIKLWD 40

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
                  ....*....|....*....|....*....|....*....
gi 1907101490 244 RQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEvRVCDSCH 282
Cdd:cd15749    14 KECGCKNCGRSFCKGCLTFSAVVPRKGNQKQ-KVCKQCH 51