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 182891424  16 LLSKIEGFQDVANTAVIIPKEDGVISVSQDRTIRVWlKRDSGQYWPSVY-HTMPVACsCMSFNPETRRISVGlENGTVSE 94
Cdd:cd00200    1 LRRTLKGHTGGVTCVAFSPDGKLLATGSGDGTIKVW-DLETGELLRTLKgHTGPVRD-VAASADGTYLASGS-SDKTIRL 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424  95 FvlseDYNQMTPARTYQAHQGGVTVVLFVLEMEWVLSTGQDKSFTWHCSESGQQLGTYRT-TAWVSGLQFDVETRHAFVG 173
Cdd:cd00200   78 W----DLETGECVRTLTGHTSYVSSVAFSPDGRILSSSSRDKTIKVWDVETGKCLTTLRGhTDWVNSVAFSPDGTFVASS 153

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424 174 DHSGQVTILKLEqdNCSLVTTFKGHTGNVTALCWDPVQRVLFSGSSDHSIIMWDIggRKGTAI-ELQGHNDKVQGLCYAP 252
Cdd:cd00200  154 SQDGTIKLWDLR--TGKCVATLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLWDL--STGKCLgTLRGHENGVNSVAFSP 229

                        250       260
                 ....*....|....*....|
gi 182891424 253 HTRQLISCGSDGGIVIWNMD 272
Cdd:cd00200  230 DGYLLASGSEDGTIRVWDLR 249

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 182891424  16 LLSKIEGFQDVANTAVIIPKEDGVISVSQDRTIRVWlKRDSGQYWPSVY-HTMPVACsCMSFNPETRRISVGlENGTVSE 94
Cdd:cd00200    1 LRRTLKGHTGGVTCVAFSPDGKLLATGSGDGTIKVW-DLETGELLRTLKgHTGPVRD-VAASADGTYLASGS-SDKTIRL 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424  95 FvlseDYNQMTPARTYQAHQGGVTVVLFVLEMEWVLSTGQDKSFTWHCSESGQQLGTYRT-TAWVSGLQFDVETRHAFVG 173
Cdd:cd00200   78 W----DLETGECVRTLTGHTSYVSSVAFSPDGRILSSSSRDKTIKVWDVETGKCLTTLRGhTDWVNSVAFSPDGTFVASS 153

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424 174 DHSGQVTILKLEqdNCSLVTTFKGHTGNVTALCWDPVQRVLFSGSSDHSIIMWDIggRKGTAI-ELQGHNDKVQGLCYAP 252
Cdd:cd00200  154 SQDGTIKLWDLR--TGKCVATLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLWDL--STGKCLgTLRGHENGVNSVAFSP 229

                        250       260
                 ....*....|....*....|
gi 182891424 253 HTRQLISCGSDGGIVIWNMD 272
Cdd:cd00200  230 DGYLLASGSEDGTIRVWDLR 249

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 182891424   279 PEWLD---SDSCQKCEQPFSWNfkqmwdskkigLRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSCHDLI 351
Cdd:smart00064   2 PHWIPdeeVSNCMGCGKEFNLT-----------KRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYENL 66

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

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 182891424   190 SLVTTFKGHTGNVTALCWDPVQRVLFSGSSDHSIIMWD 227
Cdd:smart00320   3 ELLKTLKGHTGPVTSVAFSPDGKYLASGSDDGTIKLWD 40

phosphatidylinositol kinase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424  279 PEWL----DSDSCQKCEQPFswnfkqMWDSKKIGLRQHHCRKCGQAVCGKCSSKRS-------TIPLMGFEFEVR-VCDS 346
Cdd:PTZ00303  451 PSWQkddeSSDSCPSCGRAF------ISLSRPLGTRAHHCRSCGIRLCVFCITKRAhysfaklAKPGSSDEAEERlVCDT 524

                  ..
gi 182891424  347 CH 348
Cdd:PTZ00303  525 CY 526

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 182891424 279 PEWLDSDSCQKCEQPFSWNFKQMWDSKKIGLRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSCHDLITDE 354
Cdd:cd15756    1 PQWLESDSCQKCEQPFFWNIKQMWDTKTLGLRQHHCRKCGQAVCGKCSSKRSSYPIMGFEFQVRVCDSCFETIKDE 76

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 182891424  16 LLSKIEGFQDVANTAVIIPKEDGVISVSQDRTIRVWlKRDSGQYWPSVY-HTMPVACsCMSFNPETRRISVGlENGTVSE 94
Cdd:cd00200    1 LRRTLKGHTGGVTCVAFSPDGKLLATGSGDGTIKVW-DLETGELLRTLKgHTGPVRD-VAASADGTYLASGS-SDKTIRL 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424  95 FvlseDYNQMTPARTYQAHQGGVTVVLFVLEMEWVLSTGQDKSFTWHCSESGQQLGTYRT-TAWVSGLQFDVETRHAFVG 173
Cdd:cd00200   78 W----DLETGECVRTLTGHTSYVSSVAFSPDGRILSSSSRDKTIKVWDVETGKCLTTLRGhTDWVNSVAFSPDGTFVASS 153

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424 174 DHSGQVTILKLEqdNCSLVTTFKGHTGNVTALCWDPVQRVLFSGSSDHSIIMWDIggRKGTAI-ELQGHNDKVQGLCYAP 252
Cdd:cd00200  154 SQDGTIKLWDLR--TGKCVATLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLWDL--STGKCLgTLRGHENGVNSVAFSP 229

                        250       260
                 ....*....|....*....|
gi 182891424 253 HTRQLISCGSDGGIVIWNMD 272
Cdd:cd00200  230 DGYLLASGSEDGTIRVWDLR 249

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 182891424  71 CSCMSFNPETRRISVGLENGTVSEFvlseDYNQMTPARTYQAHQGGVTVVLFVLEMEWVLSTGQDKS---FTWhcsESGQ 147
Cdd:cd00200   12 VTCVAFSPDGKLLATGSGDGTIKVW----DLETGELLRTLKGHTGPVRDVAASADGTYLASGSSDKTirlWDL---ETGE 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424 148 QLGTYRT-TAWVSGLQFDVETRHAFVGDHSGQVTILKLEQDNCslVTTFKGHTGNVTALCWDPVQRVLFSGSSDHSIIMW 226
Cdd:cd00200   85 CVRTLTGhTSYVSSVAFSPDGRILSSSSRDKTIKVWDVETGKC--LTTLRGHTDWVNSVAFSPDGTFVASSSQDGTIKLW 162

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|
gi 182891424 227 DIGGRKGTAiELQGHNDKVQGLCYAPHTRQLISCGSDGGIVIWNMDVTRQ 276
Cdd:cd00200  163 DLRTGKCVA-TLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLWDLSTGKC 211

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        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424 280 EWLDSDSCQKCEQPFSwnfkqmwdskkIGLRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSCHD 349
Cdd:cd15720    1 EWKDGDECHRCRVQFG-----------VFQRKHHCRACGQVFCGKCSSKSSTIPKFGIEKEVRVCDPCYE 59

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 182891424   279 PEWLD---SDSCQKCEQPFSWNfkqmwdskkigLRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSCHDLI 351
Cdd:smart00064   2 PHWIPdeeVSNCMGCGKEFNLT-----------KRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYENL 66

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 182891424  279 PEWL---DSDSCQKCEQPFSWNFkqmwdskkiglRQHHCRKCGQAVCGKCSSKR-STIPLMGFEFEVRVCDSCHDLIT 352
Cdd:pfam01363   1 PVWVpdsSATVCMICSKPFTFFR-----------RRHHCRNCGRVFCSACSSKKiSLLPELGSNKPVRVCDACYDTLQ 67

FYVE domain found in early endosome antigen 1 (EEA1) and similar proteins; EEA1, also termed endosome-associated protein p162, or zinc finger FYVE domain-containing protein 2, is an essential component of the endosomal fusion machinery and required for the fusion and maturation of early endosomes in endocytosis. It forms a parallel coiled-coil homodimer in cells. EEA1 serves as the p97 ATPase substrate and the p97 ATPase may regulate the size of early endosomes by governing the oligomeric state of EEA1. It can interact with the GTP-bound form of Rab22a and be involved in endosomal membrane trafficking. EEA1 also functions as an obligate scaffold for angiotensin II-induced Akt activation in early endosomes. It can be phosphorylated by p38 mitogen-activated protein kinase (MAPK) and further regulate mu opioid receptor endocytosis. EEA1 consists of an N-terminal C2H2 Zn2+ finger, four long heptad repeats, and a C-terminal region containing a calmodulin binding (IQ) motif, a Rab5 interaction site, and a FYVE domain. This model corresponds to the FYVE domain that is responsible for binding phosphatidyl inositol-3-phosphate (PtdIns3P or PI3P) on the membrane.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 182891424 279 PEWLD---SDSCQKCEQPFSwnfkqmwdskkIGLRQHHCRKCGQAVCGKCSSKRSTIPLMgfEFEVRVCDSCHDLI 351
Cdd:cd15730    1 RKWADdeeVQNCMACGKGFS-----------VTVRKHHCRQCGNIFCNECSSKTATTPSS--KKPVRVCDACFDDL 63

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 182891424 286 SCQKCEQPFSWNFkqmwdskkiglRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSCH 348
Cdd:cd00065    1 RCMLCGKKFSLFR-----------RRHHCRRCGRVFCSKCSSKKLPLPSFGSGKPVRVCDSCY 52

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        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 182891424 283 DSD--SCQKCEQPFSWNfkqmwdskkigLRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSC 347
Cdd:cd15734    5 DSEikECSVCKRPFSPR-----------LSKHHCRACGQGVCDDCSKNRRPVPSRGWDHPVRVCDPC 60

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 182891424 281 WLDSDS---CQKCEQPFSwnfkqmwdskkIGLRQHHCRKCGQAVCGKCSSKRSTIPlmGFEFEVRVCDSCHDLI 351
Cdd:cd15758    6 WLKDDEathCKQCEKEFS-----------ISRRKHHCRNCGHIFCNTCSSNELALP--SYPKPVRVCDSCHTLL 66

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 182891424 281 WLDSD---SCQKCEQPFSwnfkqmwdskkIGLRQHHCRKCGQAVCGKCSSkrSTIPLMGFEFEVRVCDSCH 348
Cdd:cd15721    1 WADDKevtHCQQCEKEFS-----------LSRRKHHCRNCGGIFCNSCSD--NTMPLPSSAKPVRVCDTCY 58

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 182891424 279 PEWLDSDSCQKCEqpfswNFKQMWDSKKiglRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSC 347
Cdd:cd15727    2 PPWVPDKECPVCM-----SCKKKFDFFK---RRHHCRRCGKCFCSDCCSNKVPLPRMCFVDPVRVCNEC 62

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 182891424 285 DSCQKCEQPFSwnfkqmwdskkIGLRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSCH 348
Cdd:cd15719   10 DSCTGCSVRFS-----------LTERRHHCRNCGQLFCSKCSRFESEIRRLRISRPVRVCQACY 62

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 182891424 281 WLDSDSCQ---KCEQPFSwNFKqmwdskkiglRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSCH 348
Cdd:cd15725    2 WMPDSSCKecyECSEKFT-TFR----------RRHHCRLCGQIFCSRCCNQEIPGKFIGYPGDLRVCTYCC 61

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
                 ....*....|....*....|....*....|....*....|
gi 182891424 310 RQHHCRKCGQAVCGKCSSKRSTIPLMGfEFEVRVCDSCHD 349
Cdd:cd15724   23 RRHHCRRCGRVVCSSCSTKKMLVEGYR-ENPVRVCDQCYE 61

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
                 ....*....|....*....|....*....|....*....|..
gi 182891424 307 IGLRQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSCH 348
Cdd:cd15733   19 LAKRKHHCRNCGNVFCADCSNYKLPIPDEQLYDPVRVCNSCY 60

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

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 182891424   190 SLVTTFKGHTGNVTALCWDPVQRVLFSGSSDHSIIMWD 227
Cdd:smart00320   3 ELLKTLKGHTGPVTSVAFSPDGKYLASGSDDGTIKLWD 40

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 182891424 284 SDSCQKCEQPfswNFKQMwdskkigLRQHHCRKCGQAVCGKCSSKRSTIPLMGFEfEVRVCDSCH 348
Cdd:cd15754    8 TDICMRCTQT---NFSLL-------TRRHHCRKCGFVVCHECSRQRFLIPRLSPK-PVRVCSLCY 61

WD domain, G-beta repeat;

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 182891424  190 SLVTTFKGHTGNVTALCWDPVQRVLFSGSSDHSIIMWD 227
Cdd:pfam00400   2 KLLKTLEGHTGSVTSLAFSPDGKLLASGSDDGTVKVWD 39

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 182891424 281 WLD---SDSCQKCEQPFswnfkqmWDSkkigLRQHHCRKCGQAVCGKCSSKRSTIP-LMGFEfEVRVCDSC 347
Cdd:cd15732    2 WVPdhlAASCYGCEREF-------WLA----SRKHHCRNCGNVFCGSCCNQKLPVPsQQLFE-PSRVCKSC 60

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 182891424 310 RQHHCRKCGQAVCGKCSSKRSTIPLMG------FEFEVRVCDSCHDLI 351
Cdd:cd15723   15 KRRSCNNCGNAFCSRCCSKKVPRSVMGatapaaQRETVFVCSGCNDKL 62

phosphatidylinositol kinase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424  279 PEWL----DSDSCQKCEQPFswnfkqMWDSKKIGLRQHHCRKCGQAVCGKCSSKRS-------TIPLMGFEFEVR-VCDS 346
Cdd:PTZ00303  451 PSWQkddeSSDSCPSCGRAF------ISLSRPLGTRAHHCRSCGIRLCVFCITKRAhysfaklAKPGSSDEAEERlVCDT 524

                  ..
gi 182891424  347 CH 348
Cdd:PTZ00303  525 CY 526

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 182891424 309 LRQHHCRKCGQAVCGKCSskRSTIPLMGFEFEV-RVCDSCH 348
Cdd:cd15742   23 LRRHHCHACGKIVCRNCS--RNKYPLKYLKDRPaKVCDGCF 61

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
                 ....*....|....*....|....*....|....*....|.
gi 182891424 310 RQHHCRKCGQAVCGKCSSkrstiplmGFEFEVRVCDSCHDL 350
Cdd:cd15716   25 RRHHCRLCGSIMCNKCSQ--------FLPLHIRCCHHCKDL 57

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 182891424 310 RQHHCRKCGQAVCGKCSSKRSTIPLMGFEFEVRVCDSCH 348
Cdd:cd15738   23 KKHHCWRCGNVFCTRCIDKQRALPGHLSQRPVPVCRACY 61

coronin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182891424 177 GQVTILKLE-QDNCSLVTTFKGHTGNVTALCWDPV-QRVLFSGSSDHSIIMWDIGGRKGTAIE-------LQGHNDKVQG 247
Cdd:PTZ00420  51 GLIGAIRLEnQMRKPPVIKLKGHTSSILDLQFNPCfSEILASGSEDLTIRVWEIPHNDESVKEikdpqciLKGHKKKISI 130

                         90       100
                 ....*....|....*....|....*.
gi 182891424 248 LCYAPHTRQLI-SCGSDGGIVIWNMD 272
Cdd:PTZ00420 131 IDWNPMNYYIMcSSGFDSFVNIWDIE 156