FYV1_MOUSE
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 03-AUG-2022, entry version 193.
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,
GN Pip5k3 {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};
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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 SWISS-2DPAGE; Q9Z1T6; -.
DR EPD; Q9Z1T6; -.
DR jPOST; Q9Z1T6; -.
DR MaxQB; Q9Z1T6; -.
DR PaxDb; Q9Z1T6; -.
DR PeptideAtlas; Q9Z1T6; -.
DR PRIDE; Q9Z1T6; -.
DR ProteomicsDB; 273396; -. [Q9Z1T6-2]
DR ProteomicsDB; 273397; -. [Q9Z1T6-1]
DR ProteomicsDB; 273398; -. [Q9Z1T6-3]
DR Antibodypedia; 34200; 370 antibodies from 34 providers.
DR DNASU; 18711; -.
DR Ensembl; ENSMUST00000097707; ENSMUSP00000095314; ENSMUSG00000025949. [Q9Z1T6-2]
DR GeneID; 18711; -.
DR KEGG; mmu:18711; -.
DR UCSC; uc007bho.1; mouse. [Q9Z1T6-3]
DR UCSC; uc007bht.1; mouse. [Q9Z1T6-2]
DR CTD; 200576; -.
DR MGI; MGI:1335106; Pikfyve.
DR VEuPathDB; HostDB:ENSMUSG00000025949; -.
DR eggNOG; KOG0230; Eukaryota.
DR GeneTree; ENSGT00940000156307; -.
DR InParanoid; Q9Z1T6; -.
DR OrthoDB; 227882at2759; -.
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 63 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 228 other tissues.
DR ExpressionAtlas; Q9Z1T6; baseline and differential.
DR Genevisible; Q9Z1T6; MM.
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; cd17300; PIPKc_PIKfyve; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR Gene3D; 3.30.800.10; -; 1.
DR Gene3D; 3.50.7.10; -; 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; IPR002498; PInositol-4-P-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; PTHR46715; 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; SSF46785; SSF46785; 1.
DR SUPFAM; SSF52029; SSF52029; 1.
DR SUPFAM; SSF54849; SSF54849; 1.
DR SUPFAM; SSF57903; SSF57903; 1.
DR PROSITE; PS50186; DEP; 1.
DR PROSITE; PS51455; PIPK; 1.
DR PROSITE; PS50178; ZF_FYVE; 1.
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
