ID FYV1_MOUSE Reviewed; 2097 AA. AC Q9Z1T6; E9QL40; Q3TNE4; Q3UTT6; Q69ZU1; Q9CU94; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 3. DT 27-MAR-2024, entry version 201. DE RecName: Full=1-phosphatidylinositol 3-phosphate 5-kinase {ECO:0000305}; DE Short=Phosphatidylinositol 3-phosphate 5-kinase; DE EC=2.7.1.150 {ECO:0000269|PubMed:10567352}; DE AltName: Full=FYVE finger-containing phosphoinositide kinase; DE AltName: Full=PIKfyve; DE AltName: Full=Phosphatidylinositol 3-phosphate 5-kinase type III; DE Short=PIPkin-III; DE Short=Type III PIP kinase; DE AltName: Full=Serine-protein kinase PIKFYVE {ECO:0000303|PubMed:11123925}; DE EC=2.7.11.1 {ECO:0000269|PubMed:11123925}; DE AltName: Full=p235 {ECO:0000303|PubMed:10419465}; GN Name=Pikfyve {ECO:0000312|MGI:MGI:1335106}; GN Synonyms=Fab1 {ECO:0000303|PubMed:19037259}, Kiaa0981, Pip5k3 GN {ECO:0000303|PubMed:19037259}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND CHARACTERIZATION. RC TISSUE=Adipose tissue; RX PubMed=9858586; DOI=10.1128/mcb.19.1.623; RA Shisheva A., Sbrissa D., Ikonomov O.; RT "Cloning, characterization, and expression of a novel Zn2+-binding FYVE RT finger-containing phosphoinositide kinase in insulin-sensitive cells."; RL Mol. Cell. Biol. 19:623-634(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Pancreatic islet; RX PubMed=15368895; DOI=10.1093/dnares/11.3.205; RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S., RA Saga Y., Seino S., Nishimura M., Kaisho T., Hoshino K., Kitamura H., RA Nagase T., Ohara O., Koga H.; RT "Prediction of the coding sequences of mouse homologues of KIAA gene: IV. RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs RT identified by screening of terminal sequences of cDNA clones randomly RT sampled from size-fractionated libraries."; RL DNA Res. 11:205-218(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC STRAIN=C57BL/6J; TISSUE=Cerebellum, Ovary, Spleen, and Uterus; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [5] RP CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=10567352; DOI=10.1074/jbc.274.48.33905; RA McEwen R.K., Dove S.K., Cooke F.T., Painter G.F., Holmes A.B., Shisheva A., RA Ohya Y., Parker P.J., Michell R.H.; RT "Complementation analysis in PtdInsP kinase-deficient yeast mutants RT demonstrates that Schizosaccharomyces pombe and murine Fab1p homologues are RT phosphatidylinositol 3-phosphate 5-kinases."; RL J. Biol. Chem. 274:33905-33912(1999). RN [6] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=10419465; DOI=10.1074/jbc.274.31.21589; RA Sbrissa D., Ikonomov O.C., Shisheva A.; RT "PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5- RT phosphoinositides. Effect of insulin."; RL J. Biol. Chem. 274:21589-21597(1999). RN [7] RP CATALYTIC ACTIVITY, FUNCTION, MUTAGENESIS OF LYS-1831, PHOSPHORYLATION, AND RP COFACTOR. RX PubMed=11123925; DOI=10.1021/bi001897f; RA Sbrissa D., Ikonomov O.C., Shisheva A.; RT "PIKfyve lipid kinase is a protein kinase: downregulation of 5'- RT phosphoinositide product formation by autophosphorylation."; RL Biochemistry 39:15980-15989(2000). RN [8] RP FUNCTION, INTERACTION WITH RABEPK, MUTAGENESIS OF LYS-1831, AND REGION. RX PubMed=14530284; DOI=10.1074/jbc.m307260200; RA Ikonomov O.C., Sbrissa D., Mlak K., Deeb R., Fligger J., Soans A., RA Finley R.L. Jr., Shisheva A.; RT "Active PIKfyve associates with and promotes the membrane attachment of the RT late endosome-to-trans-Golgi network transport factor Rab9 effector p40."; RL J. Biol. Chem. 278:50863-50871(2003). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=17242355; DOI=10.1073/pnas.0609836104; RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; RT "Large-scale phosphorylation analysis of mouse liver."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). RN [10] RP TISSUE SPECIFICITY. RX PubMed=17956977; DOI=10.1073/pnas.0702275104; RA Zhang Y., Zolov S.N., Chow C.Y., Slutsky S.G., Richardson S.C., Piper R.C., RA Yang B., Nau J.J., Westrick R.J., Morrison S.J., Meisler M.H., RA Weisman L.S.; RT "Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol RT 3,5-bisphosphate, results in neurodegeneration in mice."; RL Proc. Natl. Acad. Sci. U.S.A. 104:17518-17523(2007). RN [11] RP FUNCTION, MUTAGENESIS OF LYS-1831, AND INTERACTION WITH EGFR. RX PubMed=17909029; DOI=10.1158/0008-5472.can-07-1333; RA Kim J., Jahng W.J., Di Vizio D., Lee J.S., Jhaveri R., Rubin M.A., RA Shisheva A., Freeman M.R.; RT "The phosphoinositide kinase PIKfyve mediates epidermal growth factor RT receptor trafficking to the nucleus."; RL Cancer Res. 67:9229-9237(2007). RN [12] RP IDENTIFICATION IN THE PI(3,5)P2 REGULATORY COMPLEX, FUNCTION, AND RP SUBCELLULAR LOCATION. RX PubMed=19037259; DOI=10.1038/emboj.2008.248; RA Jin N., Chow C.Y., Liu L., Zolov S.N., Bronson R., Davisson M., RA Petersen J.L., Zhang Y., Park S., Duex J.E., Goldowitz D., Meisler M.H., RA Weisman L.S.; RT "VAC14 nucleates a protein complex essential for the acute interconversion RT of PI3P and PI(3,5)P(2) in yeast and mouse."; RL EMBO J. 27:3221-3234(2008). RN [13] RP FUNCTION, AND INTERACTION WITH SPAG9. RX PubMed=19056739; DOI=10.1074/jbc.m806539200; RA Ikonomov O.C., Fligger J., Sbrissa D., Dondapati R., Mlak K., Deeb R., RA Shisheva A.; RT "Kinesin adapter JLP links PIKfyve to microtubule-based endosome-to-trans- RT Golgi network traffic of furin."; RL J. Biol. Chem. 284:3750-3761(2009). RN [14] RP PHOSPHORYLATION AT SER-318. RX PubMed=20513353; DOI=10.1016/j.bbrc.2010.05.134; RA Hill E.V., Hudson C.A., Vertommen D., Rider M.H., Tavare J.M.; RT "Regulation of PIKfyve phosphorylation by insulin and osmotic stress."; RL Biochem. Biophys. Res. Commun. 397:650-655(2010). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-299; SER-312; SER-475 AND RP SER-1753, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Kidney, Liver, Lung, Pancreas, Spleen, and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [16] RP DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, AND CATALYTIC ACTIVITY. RX PubMed=21349843; DOI=10.1074/jbc.m111.222364; RA Ikonomov O.C., Sbrissa D., Delvecchio K., Xie Y., Jin J.P., Rappolee D., RA Shisheva A.; RT "The phosphoinositide kinase PIKfyve is vital in early embryonic RT development: preimplantation lethality of PIKfyve-/- embryos but normality RT of PIKfyve+/- mice."; RL J. Biol. Chem. 286:13404-13413(2011). RN [17] RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION. RX PubMed=22621786; DOI=10.1152/ajpcell.00105.2012; RA Sbrissa D., Ikonomov O.C., Filios C., Delvecchio K., Shisheva A.; RT "Functional dissociation between PIKfyve-synthesized PtdIns5P and RT PtdIns(3,5)P2 by means of the PIKfyve inhibitor YM201636."; RL Am. J. Physiol. 303:C436-C446(2012). RN [18] RP FUNCTION, DISRUPTION PHENOTYPE, AND CATALYTIC ACTIVITY. RX PubMed=23673157; DOI=10.1152/ajpendo.00030.2013; RA Ikonomov O.C., Sbrissa D., Delvecchio K., Feng H.Z., Cartee G.D., Jin J.P., RA Shisheva A.; RT "Muscle-specific Pikfyve gene disruption causes glucose intolerance, RT insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber- RT type switching."; RL Am. J. Physiol. 305:E119-E131(2013). RN [19] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=25178411; DOI=10.1038/ncomms5691; RA Min S.H., Suzuki A., Stalker T.J., Zhao L., Wang Y., McKennan C., RA Riese M.J., Guzman J.F., Zhang S., Lian L., Joshi R., Meng R., RA Seeholzer S.H., Choi J.K., Koretzky G., Marks M.S., Abrams C.S.; RT "Loss of PIKfyve in platelets causes a lysosomal disease leading to RT inflammation and thrombosis in mice."; RL Nat. Commun. 5:4691-4691(2014). RN [20] RP FUNCTION. RX PubMed=27623384; DOI=10.1016/j.devcel.2016.08.001; RA Krishna S., Palm W., Lee Y., Yang W., Bandyopadhyay U., Xu H., Florey O., RA Thompson C.B., Overholtzer M.; RT "PIKfyve Regulates Vacuole Maturation and Nutrient Recovery following RT Engulfment."; RL Dev. Cell 38:536-547(2016). RN [21] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=28779020; DOI=10.4049/jimmunol.1601466; RA Dayam R.M., Sun C.X., Choy C.H., Mancuso G., Glogauer M., Botelho R.J.; RT "The Lipid Kinase PIKfyve Coordinates the Neutrophil Immune Response RT through the Activation of the Rac GTPase."; RL J. Immunol. 199:2096-2105(2017). RN [22] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=29584722; DOI=10.1371/journal.pgen.1007290; RA Liggins M.C., Flesher J.L., Jahid S., Vasudeva P., Eby V., Takasuga S., RA Sasaki J., Sasaki T., Boissy R.E., Ganesan A.K.; RT "PIKfyve regulates melanosome biogenesis."; RL PLoS Genet. 14:e1007290-e1007290(2018). RN [23] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=31427458; DOI=10.1128/mcb.00158-19; RA Min S.H., Suzuki A., Weaver L., Guzman J., Chung Y., Jin H., Gonzalez F., RA Trasorras C., Zhao L., Spruce L.A., Seeholzer S.H., Behrens E.M., RA Abrams C.S.; RT "PIKfyve Deficiency in Myeloid Cells Impairs Lysosomal Homeostasis in RT Macrophages and Promotes Systemic Inflammation in Mice."; RL Mol. Cell. Biol. 39:0-0(2019). CC -!- FUNCTION: Dual specificity kinase implicated in myriad essential CC cellular processes such as maintenance of endomembrane homeostasis, and CC endocytic-vacuolar pathway, lysosomal trafficking, nuclear transport, CC stress- or hormone-induced signaling and cell cycle progression CC (PubMed:19037259, PubMed:22621786, PubMed:17909029). The PI(3,5)P2 CC regulatory complex regulates both the synthesis and turnover of CC phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Sole enzyme to CC catalyze the phosphorylation of phosphatidylinositol 3-phosphate on the CC fifth hydroxyl of the myo-inositol ring, to form (PtdIns(3,5)P2) CC (PubMed:10567352, PubMed:10419465). Also catalyzes the phosphorylation CC of phosphatidylinositol on the fifth hydroxyl of the myo-inositol ring, CC to form phosphatidylinositol 5-phosphate (PtdIns(5)P) (PubMed:22621786, CC PubMed:10419465). Has serine-protein kinase activity and is able to CC autophosphorylate and transphosphorylate. Autophosphorylation inhibits CC its own phosphatidylinositol 3-phosphate 5-kinase activity, stimulates CC FIG4 lipid phosphatase activity and down-regulates lipid product CC formation (PubMed:11123925) (By similarity). Involved in key endosome CC operations such as fission and fusion in the course of endosomal cargo CC transport (PubMed:22621786). Required for the maturation of early into CC late endosomes, phagosomes and lysosomes (By similarity). Regulates CC vacuole maturation and nutrient recovery following engulfment of CC macromolecules, initiates the redistribution of accumulated lysosomal CC contents back into the endosome network (PubMed:27623384). Critical CC regulator of the morphology, degradative activity, and protein turnover CC of the endolysosomal system in macrophages and platelets CC (PubMed:31427458, PubMed:25178411). In neutrophils, critical to perform CC chemotaxis, generate ROS, and undertake phagosome fusion with lysosomes CC (PubMed:28779020). Plays a key role in the processing and presentation CC of antigens by major histocompatibility complex class II (MHC class II) CC mediated by CTSS (By similarity). Regulates melanosome biogenesis by CC controlling the delivery of proteins from the endosomal compartment to CC the melanosome (PubMed:29584722). Essential for systemic glucose CC homeostasis, mediates insulin-induced signals for endosome/actin CC remodeling in the course of GLUT4 translocation/glucose uptake CC activation (PubMed:23673157, PubMed:22621786). Supports microtubule- CC based endosome-to-trans-Golgi network cargo transport, trhough CC association with SPAG9 and RABEPK (PubMed:19056739, PubMed:14530284). CC Mediates EGFR trafficking to the nucleus (PubMed:17909029). CC {ECO:0000250|UniProtKB:Q9Y2I7, ECO:0000269|PubMed:10419465, CC ECO:0000269|PubMed:10567352, ECO:0000269|PubMed:11123925, CC ECO:0000269|PubMed:14530284, ECO:0000269|PubMed:17909029, CC ECO:0000269|PubMed:19037259, ECO:0000269|PubMed:19056739, CC ECO:0000269|PubMed:22621786, ECO:0000269|PubMed:23673157, CC ECO:0000269|PubMed:25178411, ECO:0000269|PubMed:27623384, CC ECO:0000269|PubMed:28779020, ECO:0000269|PubMed:29584722, CC ECO:0000269|PubMed:31427458}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3- CC phosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- CC inositol-3,5-bisphosphate) + ADP + H(+); Xref=Rhea:RHEA:13609, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57923, CC ChEBI:CHEBI:58088, ChEBI:CHEBI:456216; EC=2.7.1.150; CC Evidence={ECO:0000269|PubMed:10419465, ECO:0000269|PubMed:10567352, CC ECO:0000269|PubMed:11123925, ECO:0000269|PubMed:21349843, CC ECO:0000269|PubMed:23673157}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13610; CC Evidence={ECO:0000269|PubMed:21349843, ECO:0000269|PubMed:23673157}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a CC 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + ADP + CC H(+); Xref=Rhea:RHEA:44680, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:57795, ChEBI:CHEBI:57880, ChEBI:CHEBI:456216; CC Evidence={ECO:0000269|PubMed:10419465, ECO:0000269|PubMed:21349843, CC ECO:0000269|PubMed:22621786, ECO:0000269|PubMed:23673157}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:44681; CC Evidence={ECO:0000269|PubMed:21349843, ECO:0000269|PubMed:23673157}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:11123925}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990; CC Evidence={ECO:0000305|PubMed:11123925}; CC -!- COFACTOR: CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; CC Evidence={ECO:0000269|PubMed:11123925}; CC -!- ACTIVITY REGULATION: Inhibited by apilimod and YM201636. CC {ECO:0000269|PubMed:22621786, ECO:0000269|PubMed:28779020, CC ECO:0000305|PubMed:11123925}. CC -!- SUBUNIT: Component of the PI(3,5)P2 regulatory complex/PAS complex, at CC least composed of PIKFYVE, FIG4 and VAC14. VAC14 nucleates the assembly CC of the complex and serves as a scaffold by pentamerizing into a star- CC shaped structure, which can bind a single copy each of PIKFYVE and FIG4 CC and coordinates their activities (PubMed:19037259). Interacts (via CC chaperonin-like domain) with RABEPK; the interaction recruits RABEPK to CC the endosomal membrane (PubMed:14530284). Interacts with SPAG9 CC (PubMed:19056739). Interacts with EGFR (PubMed:17909029). CC {ECO:0000250|UniProtKB:Q9Y2I7, ECO:0000269|PubMed:14530284, CC ECO:0000269|PubMed:17909029, ECO:0000269|PubMed:19037259, CC ECO:0000269|PubMed:19056739}. CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000305|PubMed:19037259, CC ECO:0000305|PubMed:21349843}; Peripheral membrane protein CC {ECO:0000269|PubMed:19037259}. Early endosome membrane CC {ECO:0000250|UniProtKB:Q9Y2I7}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:Q9Y2I7}. Cytoplasmic vesicle, phagosome membrane CC {ECO:0000250|UniProtKB:Q9Y2I7}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:Q9Y2I7}. Late endosome membrane CC {ECO:0000250|UniProtKB:Q9Y2I7}; Peripheral membrane protein CC {ECO:0000305}. Note=Mainly associated with membranes of the late CC endocytic pathway. {ECO:0000250|UniProtKB:Q9Y2I7}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=p235S; CC IsoId=Q9Z1T6-2; Sequence=Displayed; CC Name=2; Synonyms=p235L; CC IsoId=Q9Z1T6-1; Sequence=VSP_034953, VSP_034954; CC Name=3; CC IsoId=Q9Z1T6-3; Sequence=VSP_034955, VSP_034956; CC -!- TISSUE SPECIFICITY: Ubiquitous. {ECO:0000269|PubMed:17956977}. CC -!- DOMAIN: Interaction of FYVE-type domain with phosphatidylinositol 3- CC phosphate (PtdIns(3)P) is necessary for targeting to the membranes of CC the late endocytic pathway. {ECO:0000250|UniProtKB:Q9Y2I7}. CC -!- PTM: Phosphorylated in response to insulin at Ser-318 in a protein CC kinase B (PKB)-dependent manner (PubMed:20513353). Autophosphorylates CC which down-regulates lipid product formation (PubMed:11123925). CC {ECO:0000269|PubMed:11123925, ECO:0000269|PubMed:20513353}. CC -!- PTM: Autophosphorylates which inhibits its own phosphatidylinositol 3- CC phosphate 5-kinase activity, stimulates FIG4 lipid phosphatase activity CC and down-regulates lipid product formation (PubMed:11123925). CC Dephosphorylated by FIG4 in the PI(3,5)P2 regulatory complex, at Ser- CC 48, Ser-1668 and Ser-2052 (By similarity). Phosphorylated in response CC to insulin at Ser-318 in a protein kinase B (PKB)-dependent manner CC (PubMed:20513353). {ECO:0000250|UniProtKB:Q9Y2I7, CC ECO:0000269|PubMed:11123925, ECO:0000269|PubMed:20513353}. CC -!- DISRUPTION PHENOTYPE: Knockout embryos die before the 32-64-cell stage CC (PubMed:21349843). Melanocyte-specific knockout mice exhibit greying of CC the mouse coat and the accumulation of single membrane vesicle CC structures in melanocytes resembling multivesicular endosomes CC (PubMed:29584722). Myeloid cell-specific knockout micedevelop diffuse CC tissue infiltration of foamy macrophages, hepatosplenomegaly and CC systemic inflammation (PubMed:31427458). Striated muscle-specific CC knockout mice exhibit systemic glucose intolerance and insulin CC resistance at an early age but have unaltered muscle mass. From 10 CC weeks of age, mice progressively accumulate greater body weight and fat CC mass (PubMed:23673157). Platelet-specific knockout mice exhibit mild CC growth delay and body hair loss. Over time, they develop coarse facial CC features, abdominal distention, an increase in the bulk of their soft CC tissues and body weight gain. They also have decreased bone mineral CC density. As mutants aged, they remain infertile and their general body CC functions deteriorate. The majority die before 28 weeks of age. Animals CC show massive accelerated arterial thrombosis and organomegaly with CC inappropriate inflammatory responses characterized by macrophage CC accumulation in multiple tissues (PubMed:25178411). CC {ECO:0000269|PubMed:21349843, ECO:0000269|PubMed:23673157, CC ECO:0000269|PubMed:25178411, ECO:0000269|PubMed:29584722, CC ECO:0000269|PubMed:31427458}. CC -!- SEQUENCE CAUTION: CC Sequence=AAD10191.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAB30626.3; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAD32355.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF102777; AAD10191.1; ALT_FRAME; mRNA. DR EMBL; AK173077; BAD32355.1; ALT_INIT; mRNA. DR EMBL; AK017186; BAB30626.3; ALT_INIT; mRNA. DR EMBL; AK139116; BAE23894.1; -; mRNA. DR EMBL; AK165350; BAE38145.1; -; mRNA. DR EMBL; AC164079; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS35601.1; -. [Q9Z1T6-1] DR CCDS; CCDS78600.1; -. [Q9Z1T6-2] DR PIR; T18290; T18290. DR RefSeq; NP_001297553.1; NM_001310624.1. [Q9Z1T6-2] DR RefSeq; NP_035216.2; NM_011086.2. DR RefSeq; XP_006495844.1; XM_006495781.3. [Q9Z1T6-2] DR AlphaFoldDB; Q9Z1T6; -. DR SMR; Q9Z1T6; -. DR BioGRID; 202165; 7. DR CORUM; Q9Z1T6; -. DR IntAct; Q9Z1T6; 1. DR STRING; 10090.ENSMUSP00000095314; -. DR ChEMBL; CHEMBL2176842; -. DR iPTMnet; Q9Z1T6; -. DR PhosphoSitePlus; Q9Z1T6; -. DR EPD; Q9Z1T6; -. DR jPOST; Q9Z1T6; -. DR MaxQB; Q9Z1T6; -. DR PaxDb; 10090-ENSMUSP00000095314; -. DR PeptideAtlas; Q9Z1T6; -. DR ProteomicsDB; 273396; -. [Q9Z1T6-2] DR ProteomicsDB; 273397; -. [Q9Z1T6-1] DR ProteomicsDB; 273398; -. [Q9Z1T6-3] DR Pumba; Q9Z1T6; -. DR Antibodypedia; 34200; 428 antibodies from 34 providers. DR DNASU; 18711; -. DR Ensembl; ENSMUST00000097707.5; ENSMUSP00000095314.5; ENSMUSG00000025949.17. [Q9Z1T6-2] DR GeneID; 18711; -. DR KEGG; mmu:18711; -. DR UCSC; uc007bho.1; mouse. [Q9Z1T6-3] DR UCSC; uc007bht.1; mouse. [Q9Z1T6-2] DR AGR; MGI:1335106; -. DR CTD; 200576; -. DR MGI; MGI:1335106; Pikfyve. DR VEuPathDB; HostDB:ENSMUSG00000025949; -. DR eggNOG; KOG0230; Eukaryota. DR GeneTree; ENSGT00940000156307; -. DR InParanoid; Q9Z1T6; -. DR OrthoDB; 5481504at2759; -. DR PhylomeDB; Q9Z1T6; -. DR TreeFam; TF321717; -. DR BRENDA; 2.7.1.150; 3474. DR Reactome; R-MMU-1660514; Synthesis of PIPs at the Golgi membrane. DR Reactome; R-MMU-1660516; Synthesis of PIPs at the early endosome membrane. DR Reactome; R-MMU-1660517; Synthesis of PIPs at the late endosome membrane. DR BioGRID-ORCS; 18711; 6 hits in 66 CRISPR screens. DR ChiTaRS; Pikfyve; mouse. DR PRO; PR:Q9Z1T6; -. DR Proteomes; UP000000589; Chromosome 1. DR RNAct; Q9Z1T6; Protein. DR Bgee; ENSMUSG00000025949; Expressed in rostral migratory stream and 231 other cell types or tissues. DR ExpressionAtlas; Q9Z1T6; baseline and differential. DR GO; GO:0005911; C:cell-cell junction; IDA:MGI. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:MGI. DR GO; GO:0005829; C:cytosol; IDA:MGI. DR GO; GO:0031901; C:early endosome membrane; ISS:UniProtKB. DR GO; GO:0010008; C:endosome membrane; ISO:MGI. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0031902; C:late endosome membrane; TAS:Reactome. DR GO; GO:0045121; C:membrane raft; ISO:MGI. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:MGI. DR GO; GO:0030670; C:phagocytic vesicle membrane; ISS:UniProtKB. DR GO; GO:0012506; C:vesicle membrane; IDA:UniProtKB. DR GO; GO:0000285; F:1-phosphatidylinositol-3-phosphate 5-kinase activity; IDA:UniProtKB. DR GO; GO:0016308; F:1-phosphatidylinositol-4-phosphate 5-kinase activity; IDA:UniProtKB. DR GO; GO:0052810; F:1-phosphatidylinositol-5-kinase activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016301; F:kinase activity; IDA:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:1903100; P:1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate metabolic process; IDA:UniProtKB. DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; ISS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0032438; P:melanosome organization; IMP:UniProtKB. DR GO; GO:0032288; P:myelin assembly; IGI:MGI. DR GO; GO:0030593; P:neutrophil chemotaxis; IDA:UniProtKB. DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IDA:UniProtKB. DR GO; GO:0090382; P:phagosome maturation; IDA:UniProtKB. DR GO; GO:0090385; P:phagosome-lysosome fusion; IDA:UniProtKB. DR GO; GO:1904562; P:phosphatidylinositol 5-phosphate metabolic process; IDA:UniProtKB. DR GO; GO:0034504; P:protein localization to nucleus; ISO:MGI. DR GO; GO:0006612; P:protein targeting to membrane; IDA:UniProtKB. DR GO; GO:0019065; P:receptor-mediated endocytosis of virus by host cell; ISO:MGI. DR GO; GO:2000785; P:regulation of autophagosome assembly; ISO:MGI. DR GO; GO:1903426; P:regulation of reactive oxygen species biosynthetic process; IDA:UniProtKB. DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; ISO:MGI. DR CDD; cd04448; DEP_PIKfyve; 1. DR CDD; cd03334; Fab1_TCP; 1. DR CDD; cd15725; FYVE_PIKfyve_Fab1; 1. DR CDD; cd17300; PIPKc_PIKfyve; 1. DR Gene3D; 3.30.810.10; 2-Layer Sandwich; 1. DR Gene3D; 3.50.7.10; GroEL; 1. DR Gene3D; 3.30.800.10; Phosphatidylinositol Phosphate Kinase II Beta; 1. DR Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR002423; Cpn60/GroEL/TCP-1. DR InterPro; IPR000591; DEP_dom. DR InterPro; IPR027409; GroEL-like_apical_dom_sf. DR InterPro; IPR043548; PIKfyve. DR InterPro; IPR037378; PIKfyve_DEP. DR InterPro; IPR044769; PIKfyve_PIPKc. DR InterPro; IPR027483; PInositol-4-P-4/5-kinase_C_sf. DR InterPro; IPR002498; PInositol-4-P-4/5-kinase_core. DR InterPro; IPR027484; PInositol-4-P-5-kinase_N. DR InterPro; IPR027410; TCP-1-like_intermed_sf. DR InterPro; IPR036388; WH-like_DNA-bd_sf. DR InterPro; IPR036390; WH_DNA-bd_sf. DR InterPro; IPR000306; Znf_FYVE. DR InterPro; IPR017455; Znf_FYVE-rel. DR InterPro; IPR011011; Znf_FYVE_PHD. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR PANTHER; PTHR46715; 1-PHOSPHATIDYLINOSITOL 3-PHOSPHATE 5-KINASE; 1. DR PANTHER; PTHR46715:SF1; 1-PHOSPHATIDYLINOSITOL 3-PHOSPHATE 5-KINASE; 1. DR Pfam; PF00118; Cpn60_TCP1; 1. DR Pfam; PF00610; DEP; 1. DR Pfam; PF01363; FYVE; 1. DR Pfam; PF01504; PIP5K; 2. DR SMART; SM00049; DEP; 1. DR SMART; SM00064; FYVE; 1. DR SMART; SM00330; PIPKc; 1. DR SUPFAM; SSF57903; FYVE/PHD zinc finger; 1. DR SUPFAM; SSF52029; GroEL apical domain-like; 1. DR SUPFAM; SSF54849; GroEL-intermediate domain like; 1. DR SUPFAM; SSF56104; SAICAR synthase-like; 1. DR SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1. DR PROSITE; PS50186; DEP; 1. DR PROSITE; PS51455; PIPK; 1. DR PROSITE; PS50178; ZF_FYVE; 1. DR SWISS-2DPAGE; Q9Z1T6; -. DR Genevisible; Q9Z1T6; MM. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; ATP-binding; Cytoplasmic vesicle; KW Endosome; Kinase; Lipid metabolism; Membrane; Metal-binding; KW Nucleotide-binding; Phosphoprotein; Reference proteome; Transferase; Zinc; KW Zinc-finger. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT CHAIN 2..2097 FT /note="1-phosphatidylinositol 3-phosphate 5-kinase" FT /id="PRO_0000185453" FT DOMAIN 365..440 FT /note="DEP" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00066" FT DOMAIN 1757..2083 FT /note="PIPK" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00781" FT ZN_FING 158..218 FT /note="FYVE-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091" FT REGION 1..44 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 56..122 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 442..469 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 484..505 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 616..868 FT /note="Chaperonin-like domain" FT /evidence="ECO:0000269|PubMed:14530284" FT REGION 895..928 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 989..1022 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1171..1194 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1511..1555 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1697..1742 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1781..1800 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1841..2097 FT /note="Catalytic" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT COMPBIAS 1..22 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 62..91 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 94..118 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 442..461 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 990..1007 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1717..1733 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 164 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091" FT BINDING 167 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091" FT BINDING 180 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091" FT BINDING 183 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091" FT BINDING 188 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091" FT BINDING 191 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091" FT BINDING 210 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091" FT BINDING 213 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 23 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 48 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 88 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 299 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 307 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 312 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 318 FT /note="Phosphoserine; by PKB/AKT1 or PKB/AKT2" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 329 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 475 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 1543 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 1548 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 1668 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 1753 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 1968 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT MOD_RES 2052 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q9Y2I7" FT VAR_SEQ 107 FT /note="L -> LENTLPHPQEST (in isoform 2)" FT /evidence="ECO:0000303|PubMed:9858586" FT /id="VSP_034953" FT VAR_SEQ 490..545 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:9858586" FT /id="VSP_034954" FT VAR_SEQ 490..497 FT /note="NSASPSKR -> SKFGFLML (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_034955" FT VAR_SEQ 498..2097 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_034956" FT MUTAGEN 1831 FT /note="K->E: Loss of kinase activity. Decreases RABEPK FT location to membranes. Abolishes EGFR translocation to the FT nucleus." FT /evidence="ECO:0000269|PubMed:11123925, FT ECO:0000269|PubMed:14530284, ECO:0000269|PubMed:17909029" FT CONFLICT 546 FT /note="E -> K (in Ref. 1; AAD10191)" FT /evidence="ECO:0000305" FT CONFLICT 944 FT /note="K -> Q (in Ref. 2; BAD32355)" FT /evidence="ECO:0000305" FT CONFLICT 994..995 FT /note="QP -> HR (in Ref. 1; AAD10191)" FT /evidence="ECO:0000305" FT CONFLICT 1107 FT /note="R -> T (in Ref. 3; BAB30626)" FT /evidence="ECO:0000305" FT CONFLICT 1141 FT /note="L -> V (in Ref. 1; AAD10191)" FT /evidence="ECO:0000305" FT CONFLICT 1264 FT /note="S -> Y (in Ref. 1; AAD10191)" FT /evidence="ECO:0000305" FT CONFLICT 1996 FT /note="V -> E (in Ref. 1; AAD10191)" FT /evidence="ECO:0000305" SQ SEQUENCE 2097 AA; 236877 MW; 8C529E86FBEED8E6 CRC64; MATDDKSSPT LDSANDLPRS PASPSHLTHF KPLTPDQDEP PFKSAYSSFV NLFRFNKERG EGGQGEQQSP SSSWASPQIP SRTQSVRSPV PYKKQLNEEL HRRSSVLDSR RKAEPACGGH DPRTAVQLRS LSTVLKRLKE IMEGKSQDSD LKQYWMPDSQ CKECYDCSEK FTTFRRRHHC RLCGQIFCSR CCNQEIPGKF MGYTGDLRAC TYCRKIALSY AHSTDSNSIG EDLNALSDST CSVSILDPSE PRTPVGSRKA SRNIFLEDDL AWQSLIHPDS SNSALSTRLV SVQEDAGKSP ARNRSASITN LSLDRSGSPM VPSYETSVSP QANRNYIRTE TTEDERKILL DSAQLKDLWK KICHHTSGME FQDHRYWLRT HPNCIVGKEL VNWLIRNGHI ATRAQAIAIG QAMVDGRWLD CVSHHDQLFR DEYALYRPLQ STEFSETPSP DSDSVNSVEG HSEPSWFKDI KFDDSDTEQI AEEGDDNLAN SASPSKRTSV SSFQSTVDSD SAASISLNVE LDNVNFHIKK PSKYPHVPPH PADQKEYLVS DTGGQQLSIS DAFIKESLFN RRVEEKSKEL PFTPLGWHHN NLELLREENE EKQAMERLLS ANHNHMMALL QQLLQNESLS SSWRDIIVSL VCQVVQTVRP DVKHQDDDMD IRQFVHIKKI PGGKKFDSVV VNGFVCTKNI AHKKMNSCIK NPKILLLKCS IEYLYREETK FTCIDPIVLQ EREFLKNYVQ RIVDVRPTLV LVEKTVSRIA QDMLLEHGIT LVINVKSQVL ERISRMTQGD LVVSMDQLLT KPHLGTCHKF YMQIFQLPNE QTKTLMFFEG CPQHLGCTIK LRGGSDYELA RVKEILIFMI CVAYHSQLEI SFLMDEFAMP PTLMQSPSFH LLTEGRGEEG ASQEQVSGSS LPQDPECPRE ALSSEDSTLL ESRTVLEKGE LDNKSIPQAV ASLKHQDYTT PTCPAGIPCA LFALVPESLL PLHMDQQDAV GNEQPETSQQ TDEQQDPKSQ MKAFRDPLQD DTGMYVTEEV TSSEDQRKTY ALTFKQELKD VILCISPVIT FREPFLLTEK GMRCSTRDYF PEQIYWSPLL NKEVKEMESR RKKQLLRDLS GLQGMNGSVQ AKSIQVLPSH ELVSTRIAEH LGDSQTLGRM LADYRARGGR IQSKHLDPFV HSKDASCTSG GKSGNKTESD EERGLIPSDV IWPTKVDCLN PANHQRLCVL FSSSSAQSSN APSACVSPWI VTMEFYGKND LTLGIFLERY CFRSSYQCPS MFCDTPMVHH IRRFVHGQGC VQIILKELDS PVPGYQHTIL TYSWCRICKQ VTPVVALSNE SWSMSFAKYL ELRFYGHQYT RRANAEPCGH SIHHDYHQYF SYNQMVASFS YSPIRLLEVC VPLPKIFIKR QAPLKVSLLQ DLKDFFQKVS QVYLAVDERL ASLKTDTFSK TREEKMEDIF AQKEMEEGEF KNWTEKMQAR LMSSSVDTPQ QLQSIFESLI AKKQSLCEVL QAWNSRLQDL FQQEKGRKRP SVPPSPGRLR QGEESKINAM DTSPRNISPG LHNGEKEDRF LTTLSSQSST SSTHLQLPTP PEALAEQVVG GPTDLDSASG SEDVFDGHLL GSTDSQVKEK STMKAIFANL LPGNSYNPIP FPFDPDKHYL MYEHERVPIA VCEKEPSSII AFALSCKEYR NALEELSKAT LRNSAEEGLP ANSALDNRPK SSSPIRLPEI SGGQTNRTVE AEPQPTKKAS GMLSFFRGTA GKSPDLSSQK RETLRGADSA YYQVGQAGKE GLESQGLEPQ DEVDGGDTQK KQLTNPHVEL QFSDANAKFY CRLYYAGEFH KMREVILGSS EEEFIRSLSH SSPWQARGGK SGAAFYATED DRFILKQMPR LEVQSFLDFA PHYFNYITNA VQQKRPTALA KILGVYRIGY KNSQNNTEKK LDLLVMENLF YGRKMAQVFD LKGSLRNRNV KTDTGKESCD VVLLDENLLK MVRDNPLYIR SHSKSVLRTS IHSDAHFLSS HLIIDYSLLV GRDDTSNELV VGIIDYIRTF TWDKKLEMVV KSTGILGGQG KMPTVVSPEL YRTRFCEAMD KYFLMVPDHW TGLDLNC //