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 1370463625   2 PSPCSCMSFNPETRRLSIGLDNGTISEFilseDYNKMTPVKNYQAHQSRVTMILFVLELEWVLSTGQDKQ---FAWHCSE 78
Cdd:cd00200     9 TGGVTCVAFSPDGKLLATGSGDGTIKVW----DLETGELLRTLKGHTGPVRDVAASADGTYLASGSSDKTirlWDLETGE 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463625  79 SGQRLGGYrTSAVASgLQFDVETRHVFIGDHSGQVTILKLEQENCtlVTTFRGHTGGVTALCWDPVQRVLFSGSSDHSVI 158
Cdd:cd00200    85 CVRTLTGH-TSYVSS-VAFSPDGRILSSSSRDKTIKVWDVETGKC--LTTLRGHTDWVNSVAFSPDGTFVASSSQDGTIK 160

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1370463625 159 MWDIGGRKGTAiELQGHNDRVQALSYAQHTRQLISCGGDGGIVVWNMDVERQ 210
Cdd:cd00200   161 LWDLRTGKCVA-TLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLWDLSTGKC 211

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 1370463625   2 PSPCSCMSFNPETRRLSIGLDNGTISEFilseDYNKMTPVKNYQAHQSRVTMILFVLELEWVLSTGQDKQ---FAWHCSE 78
Cdd:cd00200     9 TGGVTCVAFSPDGKLLATGSGDGTIKVW----DLETGELLRTLKGHTGPVRDVAASADGTYLASGSSDKTirlWDLETGE 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463625  79 SGQRLGGYrTSAVASgLQFDVETRHVFIGDHSGQVTILKLEQENCtlVTTFRGHTGGVTALCWDPVQRVLFSGSSDHSVI 158
Cdd:cd00200    85 CVRTLTGH-TSYVSS-VAFSPDGRILSSSSRDKTIKVWDVETGKC--LTTLRGHTDWVNSVAFSPDGTFVASSSQDGTIK 160

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1370463625 159 MWDIGGRKGTAiELQGHNDRVQALSYAQHTRQLISCGGDGGIVVWNMDVERQ 210
Cdd:cd00200   161 LWDLRTGKCVA-TLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLWDLSTGKC 211

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 1370463625  213 PEWLD---SDSCQKCDQPFFWNfkqmwdskkigLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCHE 283
Cdd:smart00064   2 PHWIPdeeVSNCMGCGKEFNLT-----------KRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYE 64

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

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1370463625  124 TLVTTFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWD 161
Cdd:smart00320   3 ELLKTLKGHTGPVTSVAFSPDGKYLASGSDDGTIKLWD 40

phosphatidylinositol kinase; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463625  213 PEWL----DSDSCQKCDQPFfwnfkqMWDSKKIGLRQHHCRKCGKAVCGKCSSKRS-------SIPLMGFEFEVR-VCDS 280
Cdd:PTZ00303   451 PSWQkddeSSDSCPSCGRAF------ISLSRPLGTRAHHCRSCGIRLCVFCITKRAhysfaklAKPGSSDEAEERlVCDT 524

                   ...
gi 1370463625  281 CHE 283
Cdd:PTZ00303   525 CYK 527

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 1370463625 213 PEWLDSDSCQKCDQPFFWNFKQMWDSKKIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCHEAITDE 288
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 1370463625   2 PSPCSCMSFNPETRRLSIGLDNGTISEFilseDYNKMTPVKNYQAHQSRVTMILFVLELEWVLSTGQDKQ---FAWHCSE 78
Cdd:cd00200     9 TGGVTCVAFSPDGKLLATGSGDGTIKVW----DLETGELLRTLKGHTGPVRDVAASADGTYLASGSSDKTirlWDLETGE 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463625  79 SGQRLGGYrTSAVASgLQFDVETRHVFIGDHSGQVTILKLEQENCtlVTTFRGHTGGVTALCWDPVQRVLFSGSSDHSVI 158
Cdd:cd00200    85 CVRTLTGH-TSYVSS-VAFSPDGRILSSSSRDKTIKVWDVETGKC--LTTLRGHTDWVNSVAFSPDGTFVASSSQDGTIK 160

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1370463625 159 MWDIGGRKGTAiELQGHNDRVQALSYAQHTRQLISCGGDGGIVVWNMDVERQ 210
Cdd:cd00200   161 LWDLRTGKCVA-TLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLWDLSTGKC 211

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463625   6 SCMSFNPETRRLSIGLDNGTISEFilseDYNKMTPVKNYQAHQSRVTMILFVLELEWVLSTGQDKQFA-WHcSESGQRLG 84
Cdd:COG2319   208 RSVAFSPDGKLLASGSADGTVRLW----DLATGKLLRTLTGHSGSVRSVAFSPDGRLLASGSADGTVRlWD-LATGELLR 282

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463625  85 --GYRTSAVASgLQFDVETRHVFIGDHSGQVTILKLEqeNCTLVTTFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWDI 162
Cdd:COG2319   283 tlTGHSGGVNS-VAFSPDGKLLASGSDDGTVRLWDLA--TGKLLRTLTGHTGAVRSVAFSPDGKTLASGSDDGTVRLWDL 359

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....
gi 1370463625 163 GGRKGTAiELQGHNDRVQALSYAQHTRQLISCGGDGGIVVWNMD 206
Cdd:COG2319   360 ATGELLR-TLTGHTGAVTSVAFSPDGRTLASGSADGTVRLWDLA 402

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 1370463625  213 PEWLD---SDSCQKCDQPFFWNfkqmwdskkigLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCHE 283
Cdd:smart00064   2 PHWIPdeeVSNCMGCGKEFNLT-----------KRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYE 64

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 1370463625 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 1370463625  95 LQFDVETRHVFIGDHSGQVTILKLEqeNCTLVTTFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWDIGGRKgTAIELQG 174
Cdd:cd00200    15 VAFSPDGKLLATGSGDGTIKVWDLE--TGELLRTLKGHTGPVRDVAASADGTYLASGSSDKTIRLWDLETGE-CVRTLTG 91

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463625 175 HNDRVQALSYAQHTRQLISCGGDGGIVVWNmdverqetpewLDSDSCQKCdqpffwnfkqmwdskkigLRQH-----HCR 249
Cdd:cd00200    92 HTSYVSSVAFSPDGRILSSSSRDKTIKVWD-----------VETGKCLTT------------------LRGHtdwvnSVA 142

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463625 250 --KCGKAVCGkCSSKRSsiplmgfefeVRVCDscheaiTDEERaPTATFHDSKHNIVHVHFDATRGWLLTSGTDKVIKLW 327
Cdd:cd00200   143 fsPDGTFVAS-SSQDGT----------IKLWD------LRTGK-CVATLTGHTGEVNSVAFSPDGEKLLSSSSDGTIKLW 204

                  ..
gi 1370463625 328 DM 329
Cdd:cd00200   205 DL 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 1370463625 213 PEWLDSDSCQKCDQPF-FWNfkqmwdskkiglRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15735     1 PEWVDSDVCMRCRTAFtFTN------------RKHHCRNCGGVFCQQCSSKSLPLPHFGINQPVRVCDGCY 59

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 1370463625 220 SCQKCDQPFFWNFkqmwdskkiglRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd00065     1 RCMLCGKKFSLFR-----------RRHHCRRCGRVFCSKCSSKKLPLPSFGSGKPVRVCDSCY 52

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 1370463625 213 PEWLD---SDSCQKCDQPFfwnfkqmwdskKIGLRQHHCRKCGKAVCGKCSSKRSSIPLMgfEFEVRVCDSC 281
Cdd:cd15730     1 RKWADdeeVQNCMACGKGF-----------SVTVRKHHCRQCGNIFCNECSSKTATTPSS--KKPVRVCDAC 59

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1370463625 213 PEWL---DSDSCQKCDQPFfwNFKQmwdskkiglRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSC 281
Cdd:cd15731     3 PLWVpdeACPQCMACSAPF--TVLR---------RRHHCRNCGKIFCSRCSSNSVPLPRYGQMKPVRVCNHC 63

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 1370463625 215 WLDSDS---CQKCDQPFfwnfkqmwdskKIGLRQHHCRKCGKAVCGKCSSKRSSIPlmGFEFEVRVCDSCH 282
Cdd:cd15758     6 WLKDDEathCKQCEKEF-----------SISRRKHHCRNCGHIFCNTCSSNELALP--SYPKPVRVCDSCH 63

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 1370463625 210 QETPEWL-DSDS--CQKCDQPFfwnfkqmwdskKIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGfEFEVRVCDSCHEAI 285
Cdd:cd15729     2 KVAPVWVpDSEApnCMQCEVKF-----------TFTKRRHHCRACGKVLCSACCSLKARLEYLD-NKEARVCVPCYQTL 68

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463625 110 SGQVTILKLEQENCTLVTTFRGHTGGVTALCWDPVQRVLFSGSSDHSVIMWDIGGRKGTAIeLQGHNDRVQALSYAQHTR 189
Cdd:COG2319    55 AGDLTLLLLDAAAGALLATLLGHTAAVLSVAFSPDGRLLASASADGTVRLWDLATGLLLRT-LTGHTGAVRSVAFSPDGK 133

                          90
                  ....*....|....*..
gi 1370463625 190 QLISCGGDGGIVVWNMD 206
Cdd:COG2319   134 TLASGSADGTVRLWDLA 150

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 1370463625 221 CQKCDQPFFwnfkqmwdskkIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15733    10 CFGCDCEFW-----------LAKRKHHCRNCGNVFCADCSNYKLPIPDEQLYDPVRVCNSCY 60

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 1370463625 244 RQHHCRKCGKAVCGKCSSKRSSIPLMGfEFEVRVCDSCHE 283
Cdd:cd15724    23 RRHHCRRCGRVVCSSCSTKKMLVEGYR-ENPVRVCDQCYE 61

FYVE domain found in metazoan PIKfyve, fungal and plant Fab1, and similar proteins; PIKfyve, also termed FYVE finger-containing phosphoinositide kinase, or 1-phosphatidylinositol 3-phosphate 5-kinase, or phosphatidylinositol 3-phosphate 5-kinase (PIP5K3), or phosphatidylinositol 3-phosphate 5-kinase type III (PIPkin-III or type III PIP kinase), is a phosphoinositide 5-kinase that forms a complex with its regulators, the scaffolding protein Vac14 and the lipid phosphatase Fig4. The complex is responsible for synthesizing phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] from phosphatidylinositol 3-phosphate (PtdIns3P or PI3P). Then phosphatidylinositol-5-phosphate (PtdIns5P) is generated directly from PtdIns(3,5)P2. PtdIns(3,5)P2 and PtdIns5P regulate endosomal trafficking and responses to extracellular stimuli. At this point, PIKfyve is vital in early embryonic development. Moreover, PIKfyve forms a complex with ArPIKfyve (associated regulator of PIKfyve) and SAC3 at the endomembranes, which plays a role in receptor tyrosine kinase (RTK) degradation. The phosphorylation of PIKfyve by AKT can facilitate Epidermal growth factor receptor (EGFR) degradation. In addition, PIKfyve may participate in the regulation of the glutamate transporters EAAT2, EAAT3 and EAAT4, and the cystic fibrosis transmembrane conductance regulator (CFTR). It is also essential for systemic glucose homeostasis and insulin-regulated glucose uptake/GLUT4 translocation in skeletal muscle. It can be activated by protein kinase B (PKB/Akt) and further up-regulates human ether-a-go-go (hERG) channels. This family also includes the yeast and plant orthologs of human PIKfyve, Fab1. PIKfyve and its orthologs share a similar architecture. They contain an N-terminal FYVE domain, a middle region related to the CCT/TCP-1/Cpn60 chaperonins that are involved in productive folding of actin and tubulin, a second middle domain that contains a number of conserved cysteine residues (CCR) unique to this family, and a C-terminal lipid kinase domain related to PtdInsP kinases.

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                  ....*....|....*....|....*....|....*....|
gi 1370463625 244 RQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCHE 283
Cdd:cd15725    23 RRHHCRLCGQIFCSRCCNQEIPGKFIGYPGDLRVCTYCCK 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.

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                  ....*....|....*....|....*....|....*...
gi 1370463625 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 1370463625 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 1370463625 220 SCQKCDQPFFWNFKQmwdskkiglrQHHCRKCGKAVCGKCSSKRSSIPLMGFEfEVRVCDSCH 282
Cdd:cd15744     1 SCSLCQEDFASLALP----------KHNCYNCGGTFCDACSSNELPLPSSIYE-PARVCDVCY 52

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

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1370463625 217 DSDSCQKCDQPFfwnfkqmwdskKIGLRQHHCRKCGKAVCGKCSSKrsSIPLMGFEFEVRVCDSCH 282
Cdd:cd15739     9 DVDQCPNCKTPF-----------SVGKRKHHCRHCGKIFCSDCLTK--TVPSGPNRRPARVCDVCH 61

FYVE domain found in RUN and FYVE domain-containing protein 2 (RUFY2) and similar proteins; RUFY2, also termed Rab4-interacting protein related, is a novel embryonic factor that contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between. It is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1370463625 217 DSDSCQKCDQPFfwnfkqmwdskKIGLRQHHCRKCGKAVCGKCSSkrSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15759     9 EATHCKLCEKEF-----------SLSKRKHHCRNCGEIFCNACSD--NELPLPSSPKPVRVCDSCH 61

FYVE-like domain found in FYVE, RhoGEF and PH domain-containing protein 3 (FGD3) and similar proteins; FGD3, also termed zinc finger FYVE domain-containing protein 5, is a putative Cdc42-specific guanine nucleotide exchange factor (GEF) that undergoes the ubiquitin ligase SCFFWD1/beta-TrCP-mediated proteasomal degradation. It is a homologue of FGD1 and contains a DBL homology (DH) domain and pleckstrin homology (PH) domain in the middle region, a FYVE domain, and another PH domain in the C-terminus, but lacks the N-terminal proline-rich domain (PRD) found in FGD1. Due to this difference, FGD3 may play different roles from that of FGD1 to regulate cell morphology or motility. The FYVE domain of FGD3 resembles a FYVE-like domain that is different from the canonical FYVE domains, since it lacks one of the three conserved signature motifs (the WxxD motif) that are involved in phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding and exhibits altered lipid binding specificities.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1370463625 217 DSDSCQKCDQPFfwNFkqmwdskkIGLRQHHCRKCGKAVCGKCSSKRSSIPLmgfefEVRVCDSC 281
Cdd:cd15740     4 EKQTCKGCNESF--NS--------ITKRRHHCKQCGAVICGKCSEFKDLASR-----HNRVCRDC 53

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1370463625 221 CQKCDQPFfwnfkqmwdskKIGLRQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSC 281
Cdd:cd15745     2 CAICAKAF-----------SLFRRKYVCRLCGGVVCHSCSSEDLVLSVPDTCIYLRVCKTC 51

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.

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                  ....*....|....*....|....*....|....*....|....*...
gi 1370463625 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.

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                  ....*....|....*....|....*....|....*....
gi 1370463625 244 RQHHCRKCGKAVCGKCSSKRSSIPLMGFEFEVRVCDSCH 282
Cdd:cd15738    23 KKHHCWRCGNVFCTRCIDKQRALPGHLSQRPVPVCRACY 61

WD domain, G-beta repeat;

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                  ....*....|....*....|....*....|....
gi 1370463625 171 ELQGHNDRVQALSYAQHTRQLISCGGDGGIVVWN 204
Cdd:pfam00400   6 TLEGHTGSVTSLAFSPDGKLLASGSDDGTVKVWD 39

FYVE domain found in Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and FYVE-related domain 1 found in yeast protein VAC1 (Vac1p) and similar proteins; The family includes Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and protein VAC1 (Vac1p). scVps27p, also termed Golgi retention defective protein 11, is the putative yeast counterpart of the mammalian protein Hrs and is involved in endosome maturation. It is a mono-ubiquitin-binding protein that interacts with ubiquitinated cargoes, such as Hse1p, and is required for protein sorting into the multivesicular body. Vps27p forms a complex with Hse1p. The complex binds ubiquitin and mediates endosomal protein sorting. At the endosome, Vps27p and a trimeric protein complex, ESCRT-1, bind ubiquitin and are important for multivesicular body (MVB) sorting. Vps27p contains an N-terminal VHS (Vps27/Hrs/STAM) domain, a FYVE domain that binds PtdIns3P, followed by two ubiquitin-interacting motifs (UIMs), and a C-terminal clathrin-binding motif. Vac1p, also termed vacuolar segregation protein Pep7p, or carboxypeptidase Y-deficient protein 7, or vacuolar protein sorting-associated protein 19 (Vps19p), or vacuolar protein-targeting protein 19, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P)-binding protein that interacts with a Rab GTPase, GTP-bound form of Vps21p, and a Sec1p homologue, Vps45p, to facilitate Vps45p-dependent vesicle-mediated vacuolar protein sorting. It also acts as a novel regulator of vesicle docking and/or fusion at the endosome and functions in vesicle-mediated transport of Golgi precursor carboxypeptidase Y (CPY), protease A (PrA), protease B (PrB), but not alkaline phosphatase (ALP) from the trans-Golgi network-like compartment (TGN) to the endosome. Vac1p contains an N-terminal classical TFIIIA-like zinc finger, two putative zinc-binding FYVE fingers, and a C-terminal coiled coil region. The FYVE domain in both Vps27p and Vac1p harbors a zinc-binding site composed of seven Cysteines and one Histidine, which is different from that of other FYVE domain containing proteins.

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                  ....*....|....*....|....*....|....*....|....*....|
gi 1370463625 238 SKKIGL--RQHHCRKCGKAVCGKCSSKRSSIPLMGFEFE----VRVCDSC 281
Cdd:cd15736     6 SRTFNLniRAHHCRKCGKLFCRRHLPNMIPLNLSAYDPRngkwYRCCHSC 55