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 45550133 3418 DHWLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILKPVRVCQACYSQL 3482
Cdd:cd15719    1 DHWVKDEGGDSCTGCSVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRLRISRPVRVCQACYNIL 65

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 45550133 2995 KYIAWGFADHSLRIglYDTDRASFVSEaSAQNSGEILTCA-CPNAKMIVTAGTSSVVTIWkfdaNRKSLAVKHSLHGHTD 3073
Cdd:cd00200   22 KLLATGSGDGTIKV--WDLETGELLRT-LKGHTGPVRDVAaSADGTYLASGSSDKTIRLW----DLETGECVRTLTGHTS 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133 3074 AVTCLAASAAYNVIVSGSRDGTAIVWDMTRFTFVRQLRGHAGVVAAVSINELTGDIATCSA-TWLHVWSINGDALamVNT 3152
Cdd:cd00200   95 YVSSVAFSPDGRILSSSSRDKTIKVWDVETGKCLTTLRGHTDWVNSVAFSPDGTFVASSSQdGTIKLWDLRTGKC--VAT 172

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|..
gi 45550133 3153 CVGSADrmqQILCVAFSqirewDQQNVIITGSTDGVVRMWSL 3194
Cdd:cd00200  173 LTGHTG---EVNSVAFS-----PDGEKLLSSSSDGTIKLWDL 206

Beige/BEACH domain; The BEACH domain was described in the BEIGE protein (D1035670) and in the highly homologous CHS protein. The BEACH domain is usually followed by a series of WD repeats. The function of the BEACH domain is unknown.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133    2637 TQRWVRGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEELDLTNPKTFRDFSRPMGAQAEERLEQFQKRFKEW 2716
Cdd:smart01026    1 TQKWQNGEISNFEYLMHLNTLAGRSYNDLTQYPVFPWVLADYTSETLDLSNPSTFRDLSKPIGALNPERLEFFYERYEEL 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133    2717 DDPhgETPPYHYGTHYSSAMIVCSYLVRLEPFSQPFLKLQGGHFDLADRMFHSIKEAWLSASKLNMADVKELIPEFFYLP 2796
Cdd:smart01026   81 EDP--DIPPFHYGTHYSSAGIVLYYLIRLEPFTTLFLQLQGGRFDHADRLFHSVAATWRSASLESMTDVKELIPEFFYLP 158

                           170       180       190       200       210       220       230       240
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133    2797 EFLSNFNNFDLGTKQNGETLNHVILPPWAKHDPREFIRLHRSALECDYVSQHLHLWIDLIFGCKQQGPAAVDAVNVFHHL 2876
Cdd:smart01026  159 EFLVNINGFDFGTRQDGEDVDDVELPPWAKGSPEEFIRKHREALESEYVSQHLHHWIDLIFGYKQRGKEAVEALNVFHPL 238

                           250       260       270       280
                    ....*....|....*....|....*....|....*....|..
gi 45550133    2877 FYEGNVDIYNIDDPLKKNATIGFINNFGQIPKQLFKKAHPAK 2918
Cdd:smart01026  239 TYEGAVDLDSIEDPVERKALEGQIHNFGQTPKQLFKEPHPPR 280

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 45550133 3418 DHWLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILKPVRVCQACYSQL 3482
Cdd:cd15719    1 DHWVKDEGGDSCTGCSVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRLRISRPVRVCQACYNIL 65

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

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 45550133    3417 ADHWLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILKPVRVCQACYSQL 3482
Cdd:smart00064    1 RPHWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYENL 66

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 45550133 2995 KYIAWGFADHSLRIglYDTDRASFVSEaSAQNSGEILTCA-CPNAKMIVTAGTSSVVTIWkfdaNRKSLAVKHSLHGHTD 3073
Cdd:cd00200   22 KLLATGSGDGTIKV--WDLETGELLRT-LKGHTGPVRDVAaSADGTYLASGSSDKTIRLW----DLETGECVRTLTGHTS 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133 3074 AVTCLAASAAYNVIVSGSRDGTAIVWDMTRFTFVRQLRGHAGVVAAVSINELTGDIATCSA-TWLHVWSINGDALamVNT 3152
Cdd:cd00200   95 YVSSVAFSPDGRILSSSSRDKTIKVWDVETGKCLTTLRGHTDWVNSVAFSPDGTFVASSSQdGTIKLWDLRTGKC--VAT 172

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|..
gi 45550133 3153 CVGSADrmqQILCVAFSqirewDQQNVIITGSTDGVVRMWSL 3194
Cdd:cd00200  173 LTGHTG---EVNSVAFS-----PDGEKLLSSSSDGTIKLWDL 206

PH domain associated with Beige/BEACH; This PH domain is found in proteins containing the Beige/BEACH domain (pfam02138), it immediately precedes the Beige/BEACH domain.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 45550133   2530 GGTSSTTSRAVSHKLRQCSKFAYEEIREVHKRRYLLQPIALEVFSEDGRNYLLSFPRK-VRNKVNQR 2595
Cdd:pfam14844   31 ALDSVQESESLGYDKPKHKRWPISDIKEVHLRRYLLRDTALEIFLIDRTSLFFNFPDTgTRRKVYRK 97

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

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|
gi 45550133    3061 SLAVKHSLHGHTDAVTCLAASAAYNVIVSGSRDGTAIVWD 3100
Cdd:smart00320    1 SGELLKTLKGHTGPVTSVAFSPDGKYLASGSDDGTIKLWD 40

Beige/BEACH domain; The BEACH domain was described in the BEIGE protein (D1035670) and in the highly homologous CHS protein. The BEACH domain is usually followed by a series of WD repeats. The function of the BEACH domain is unknown.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133    2637 TQRWVRGEISNFQYLMHLNTLAGRSYNDLMQYPVFPWILADYDSEELDLTNPKTFRDFSRPMGAQAEERLEQFQKRFKEW 2716
Cdd:smart01026    1 TQKWQNGEISNFEYLMHLNTLAGRSYNDLTQYPVFPWVLADYTSETLDLSNPSTFRDLSKPIGALNPERLEFFYERYEEL 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133    2717 DDPhgETPPYHYGTHYSSAMIVCSYLVRLEPFSQPFLKLQGGHFDLADRMFHSIKEAWLSASKLNMADVKELIPEFFYLP 2796
Cdd:smart01026   81 EDP--DIPPFHYGTHYSSAGIVLYYLIRLEPFTTLFLQLQGGRFDHADRLFHSVAATWRSASLESMTDVKELIPEFFYLP 158

                           170       180       190       200       210       220       230       240
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133    2797 EFLSNFNNFDLGTKQNGETLNHVILPPWAKHDPREFIRLHRSALECDYVSQHLHLWIDLIFGCKQQGPAAVDAVNVFHHL 2876
Cdd:smart01026  159 EFLVNINGFDFGTRQDGEDVDDVELPPWAKGSPEEFIRKHREALESEYVSQHLHHWIDLIFGYKQRGKEAVEALNVFHPL 238

                           250       260       270       280
                    ....*....|....*....|....*....|....*....|..
gi 45550133    2877 FYEGNVDIYNIDDPLKKNATIGFINNFGQIPKQLFKKAHPAK 2918
Cdd:smart01026  239 TYEGAVDLDSIEDPVERKALEGQIHNFGQTPKQLFKEPHPPR 280

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 45550133 3418 DHWLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILKPVRVCQACYSQL 3482
Cdd:cd15719    1 DHWVKDEGGDSCTGCSVRFSLTERRHHCRNCGQLFCSKCSRFESEIRRLRISRPVRVCQACYNIL 65

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

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 45550133    3417 ADHWLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILKPVRVCQACYSQL 3482
Cdd:smart00064    1 RPHWIPDEEVSNCMGCGKEFNLTKRRHHCRNCGRIFCSKCSSKKAPLPKLGIERPVRVCDDCYENL 66

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 45550133 2995 KYIAWGFADHSLRIglYDTDRASFVSEaSAQNSGEILTCA-CPNAKMIVTAGTSSVVTIWkfdaNRKSLAVKHSLHGHTD 3073
Cdd:cd00200   22 KLLATGSGDGTIKV--WDLETGELLRT-LKGHTGPVRDVAaSADGTYLASGSSDKTIRLW----DLETGECVRTLTGHTS 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133 3074 AVTCLAASAAYNVIVSGSRDGTAIVWDMTRFTFVRQLRGHAGVVAAVSINELTGDIATCSA-TWLHVWSINGDALamVNT 3152
Cdd:cd00200   95 YVSSVAFSPDGRILSSSSRDKTIKVWDVETGKCLTTLRGHTDWVNSVAFSPDGTFVASSSQdGTIKLWDLRTGKC--VAT 172

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|..
gi 45550133 3153 CVGSADrmqQILCVAFSqirewDQQNVIITGSTDGVVRMWSL 3194
Cdd:cd00200  173 LTGHTG---EVNSVAFS-----PDGEKLLSSSSDGTIKLWDL 206

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 45550133 2992 SYTKYIAWGFADHSLRIglYDTDRASFVSEAsAQNSGEILTCAC-PNAKMIVTAGTSSVVTIWKFDANRKslavKHSLHG 3070
Cdd:cd00200   61 ADGTYLASGSSDKTIRL--WDLETGECVRTL-TGHTSYVSSVAFsPDGRILSSSSRDKTIKVWDVETGKC----LTTLRG 133

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133 3071 HTDAVTCLAASAAYNVIVSGSRDGTAIVWDMTRFTFVRQLRGHAGVVAAVSINELTGDIATCSA--TwLHVWSINGDALa 3148
Cdd:cd00200  134 HTDWVNSVAFSPDGTFVASSSQDGTIKLWDLRTGKCVATLTGHTGEVNSVAFSPDGEKLLSSSSdgT-IKLWDLSTGKC- 211

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 45550133 3149 mVNTCVGSADRmqqILCVAFSQIREWdqqnvIITGSTDGVVRMWSLE 3195
Cdd:cd00200  212 -LGTLRGHENG---VNSVAFSPDGYL-----LASGSEDGTIRVWDLR 249

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133 3420 WLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILKPVRVCQACY 3479
Cdd:cd15731    5 WVPDEACPQCMACSAPFTVLRRRHHCRNCGKIFCSRCSSNSVPLPRYGQMKPVRVCNHCF 64

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 45550133 3420 WLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRilKPVRVCQACYSQL 3482
Cdd:cd15730    3 WADDEEVQNCMACGKGFSVTVRKHHCRQCGNIFCNECSSKTATTPSSK--KPVRVCDACFDDL 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 45550133 3416 VADHWLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSrfeSEISRLRIL--KPVRVCQACYSQL 3482
Cdd:cd15729    3 VAPVWVPDSEAPNCMQCEVKFTFTKRRHHCRACGKVLCSACC---SLKARLEYLdnKEARVCVPCYQTL 68

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 45550133 3420 WLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILKPVRVCQACY 3479
Cdd:cd15733    1 WVPDHAASHCFGCDCEFWLAKRKHHCRNCGNVFCADCSNYKLPIPDEQLYDPVRVCNSCY 60

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 45550133 3420 WLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILKPVRVCQACY 3479
Cdd:cd15727    4 WVPDKECPVCMSCKKKFDFFKRRHHCRRCGKCFCSDCCSNKVPLPRMCFVDPVRVCNECA 63

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 45550133 3032 TCAC--PNAKMIVTAGTSSVVTIWKFDANRkslaVKHSLHGHTDAVTCLAASAAYNVIVSGSRDGTAIVWDMTRFTFVRQ 3109
Cdd:cd00200   13 TCVAfsPDGKLLATGSGDGTIKVWDLETGE----LLRTLKGHTGPVRDVAASADGTYLASGSSDKTIRLWDLETGECVRT 88

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45550133 3110 LRGHAGVVAAVSINELTGDIATCSA--TwLHVWSINgdalamVNTCVGS-ADRMQQILCVAFSQirewdQQNVIITGSTD 3186
Cdd:cd00200   89 LTGHTSYVSSVAFSPDGRILSSSSRdkT-IKVWDVE------TGKCLTTlRGHTDWVNSVAFSP-----DGTFVASSSQD 156

                 ....*....
gi 45550133 3187 GVVRMWSLE 3195
Cdd:cd00200  157 GTIKLWDLR 165

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 45550133 3065 KHSLHGHTDAVTCLAASAAYNVIVSGSRDGTAIVWDMTRFTFVRQLRGHAGVVAAVSINELTGDIATCSA--TwLHVWSI 3142
Cdd:cd00200    2 RRTLKGHTGGVTCVAFSPDGKLLATGSGDGTIKVWDLETGELLRTLKGHTGPVRDVAASADGTYLASGSSdkT-IRLWDL 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 45550133 3143 NGDALamVNTCVGSAdrmQQILCVAFSQIREWdqqnvIITGSTDGVVRMWSLE 3195
Cdd:cd00200   81 ETGEC--VRTLTGHT---SYVSSVAFSPDGRI-----LSSSSRDKTIKVWDVE 123

FYVE domain found in Saccharomyces cerevisiae vacuolar protein sorting-associated protein 27 (scVps27p) and similar proteins; scVps27p, also termed Golgi retention defective protein 11, is the putative yeast counterpart of the mammalian protein Hrs and is involved in endosome maturation. It is a mono-ubiquitin-binding protein that interacts with ubiquitinated cargoes, such as Hse1p, and is required for protein sorting into the multivesicular body. Vps27p forms a complex with Hse1p. The complex binds ubiquitin and mediates endosomal protein sorting. At the endosome, Vps27p and a trimeric protein complex, ESCRT-1, bind ubiquitin and are important for multivesicular body (MVB) sorting. Vps27p contains an N-terminal VHS (Vps27/Hrs/STAM) domain, a FYVE domain that binds PtdIns3P, followed by two ubiquitin-interacting motifs (UIMs), and a C-terminal clathrin-binding motif.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 45550133 3419 HWLKDegaDQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFeseisRLRILK------PVRVCQACY 3479
Cdd:cd15760    1 HWKPD---SRCDVCRKKFGLFKRRHHCRNCGDSFCSEHSSR-----RIPLPHlgplgvPQRVCDRCF 59

FYVE domain found in protein containing both PH and FYVE domains 1 (phafin-1), 2 (phafin-2), and similar proteins; This family includes protein containing both PH and FYVE domains 1 (phafin-1) and 2 (phafin-2). Phafin-1 is a representative of a novel family of PH and FYVE domain-containing proteins called phafins. It is a ubiquitously expressed pro-apoptotic protein via translocating to lysosomes, facilitating apoptosis induction through a lysosomal-mitochondrial apoptotic pathway. Phafin-2 is a ubiquitously expressed endoplasmic reticulum-associated protein that facilitates tumor necrosis factor alpha (TNF-alpha)-triggered cellular apoptosis through endoplasmic reticulum (ER)-mitochondrial apoptotic pathway. It is an endosomal phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) effector, as well as an interactor of the endosomal-tethering protein EEA1. It regulates endosome fusion upstream of Rab5. Phafin-2 also functions as a novel regulator of endocytic epidermal growth factor receptor (EGFR) degradation through a role in endosomal fusion.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 45550133 3420 WLKDEGADQCVKC-HVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRIlKPVRVCQACY 3479
Cdd:cd15717    2 WVPDSEAPVCMHCkKTKFTAINRRHHCRKCGAVVCGACSSKKFLLPHQSS-KPLRVCDTCY 61

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 45550133 3419 HWLKDEGADQCVKCHVKFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILKPVRVCQACY 3479
Cdd:cd15725    1 YWMPDSSCKECYECSEKFTTFRRRHHCRLCGQIFCSRCCNQEIPGKFIGYPGDLRVCTYCC 61

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        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 45550133 3420 WLKDEGADQCVKCH-VKFTLYERKHHCRNCGQVFCNKCSR----FESEISrlrilKPVRVCQACYSQL 3482
Cdd:cd15755    2 WVPDSEATVCMRCQkAKFTPVNRRHHCRKCGFVVCGPCSEkkflLPSQSS-----KPVRVCDFCYDLL 64

FYVE domain found in FYVE domain-containing protein 26 (ZFY26 or ZFYVE26); ZFY26, also termed FYVE domain-containing centrosomal protein (FYVE-CENT), or spastizin, is a phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) binding protein that localizes to the centrosome and midbody. ZFY26 and its interacting partners TTC19 and KIF13A are required for cytokinesis. It also interacts with Beclin 1, a subunit of class III phosphatidylinositol 3-kinase complex, and may have potential implications for carcinogenesis. In addition, it has been considered as the causal agent of a rare form of hereditary spastic paraplegia. ZFY26 contains a FYVE domain that is important for targeting of FYVE-CENT to the midbody.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 45550133 3420 WLKDEGADQCVKCHV-KFTLYERKHHCRNCGQVFCNKCSRFESEISRLRILkPVRVCQACYS 3480
Cdd:cd15724    1 WVPDEAVSVCMVCQVeRFSMFNRRHHCRRCGRVVCSSCSTKKMLVEGYREN-PVRVCDQCYE 61