ID FLCN_HUMAN Reviewed; 579 AA. AC Q8NFG4; A6NJJ8; Q6ZRX1; Q96BD2; Q96BE4; DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2002, sequence version 1. DT 02-SEP-2026, entry version 179. DE RecName: Full=Folliculin {ECO:0000303|PubMed:15657874}; DE AltName: Full=BHD skin lesion fibrofolliculoma protein {ECO:0000303|PubMed:12204536}; DE AltName: Full=Birt-Hogg-Dube syndrome protein {ECO:0000303|PubMed:12204536}; GN Name=FLCN {ECO:0000303|PubMed:15657874, ECO:0000312|HGNC:HGNC:27310}; GN Synonyms=BHD {ECO:0000303|PubMed:12204536}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL RP STAGE, AND INVOLVEMENT IN BIRT-HOGG-DUBE SYNDROME. RC TISSUE=Lung; RX PubMed=12204536; DOI=10.1016/s1535-6108(02)00104-6; RA Nickerson M.L., Warren M.B., Toro J.R., Matrosova V., Glenn G., RA Turner M.L., Duray P., Merino M., Choyke P.L., Pavlovich C.P., Sharma N., RA Walther M.M., Munroe D., Hill R., Maher E., Greenberg C., Lerman M.I., RA Linehan W.M., Zbar B., Schmidt L.S.; RT "Mutations in a novel gene lead to kidney tumors, lung wall defects, and RT benign tumors of the hair follicle in patients with the Birt-Hogg-Dube RT syndrome."; RL Cancer Cell 2:157-164(2002). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Spleen; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the RT human lineage."; RL Nature 440:1045-1049(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 267-579 (ISOFORM 1). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP POSSIBLE INVOLVEMENT IN COLORECTAL CANCER, AND VARIANTS TRP-79 AND THR-445. RX PubMed=12843323; DOI=10.1136/jmg.40.7.511; RA Kahnoski K., Khoo S.K., Nassif N.T., Chen J., Lobo G.P., Segelov E., RA Teh B.T.; RT "Alterations of the Birt-Hogg-Dube gene (BHD) in sporadic colorectal RT tumours."; RL J. Med. Genet. 40:511-515(2003). RN [7] RP POSSIBLE INVOLVEMENT IN RENAL CELL CARCINOMA AND COLORECTAL CANCER, AND RP VARIANTS VAL-238; GLN-320; GLY-392 AND SER-444. RX PubMed=14627671; DOI=10.1136/jmg.40.11.820; RA da Silva N.F., Gentle D., Hesson L.B., Morton D.G., Latif F., Maher E.R.; RT "Analysis of the Birt-Hogg-Dube (BHD) tumour suppressor gene in sporadic RT renal cell carcinoma and colorectal cancer."; RL J. Med. Genet. 40:820-824(2003). RN [8] RP INVOLVEMENT IN PSP. RX PubMed=15657874; DOI=10.1086/428455; RA Painter J.N., Tapanainen H., Somer M., Tukiainen P., Aittomaeki K.; RT "A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly RT inherited spontaneous pneumothorax."; RL Am. J. Hum. Genet. 76:522-527(2005). RN [9] RP INVOLVEMENT IN BIRT-HOGG-DUBE SYNDROME. RX PubMed=15852235; DOI=10.1086/430842; RA Schmidt L.S., Nickerson M.L., Warren M.B., Glenn G.M., Toro J.R., RA Merino M.J., Turner M.L., Choyke P.L., Sharma N., Peterson J., Morrison P., RA Maher E.R., Walther M.M., Zbar B., Linehan W.M.; RT "Germline BHD-mutation spectrum and phenotype analysis of a large cohort of RT families with Birt-Hogg-Dube syndrome."; RL Am. J. Hum. Genet. 76:1023-1033(2005). RN [10] RP FUNCTION, PHOSPHORYLATION, SUBCELLULAR LOCATION, INTERACTION WITH FNIP1, RP AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17028174; DOI=10.1073/pnas.0603781103; RA Baba M., Hong S.-B., Sharma N., Warren M.B., Nickerson M.L., Iwamatsu A., RA Esposito D., Gillette W.K., Hopkins R.F. III, Hartley J.L., Furihata M., RA Oishi S., Zhen W., Burke T.R. Jr., Linehan W.M., Schmidt L.S., Zbar B.; RT "Folliculin encoded by the BHD gene interacts with a binding protein, RT FNIP1, and AMPK, and is involved in AMPK and mTOR signaling."; RL Proc. Natl. Acad. Sci. U.S.A. 103:15552-15557(2006). RN [11] RP INVOLVEMENT IN PSP. RX PubMed=17496196; DOI=10.1136/jmg.2007.049874; RA Gunji Y., Akiyoshi T., Sato T., Kurihara M., Tominaga S., Takahashi K., RA Seyama K.; RT "Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts RT and recurrent pneumothorax."; RL J. Med. Genet. 44:588-593(2007). RN [12] RP INTERACTION WITH FNIP2. RX PubMed=18403135; DOI=10.1016/j.gene.2008.02.022; RA Hasumi H., Baba M., Hong S.-B., Hasumi Y., Huang Y., Yao M., Valera V.A., RA Linehan W.M., Schmidt L.S.; RT "Identification and characterization of a novel folliculin-interacting RT protein FNIP2."; RL Gene 415:60-67(2008). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FNIP2. RX PubMed=18663353; DOI=10.1038/onc.2008.261; RA Takagi Y., Kobayashi T., Shiono M., Wang L., Piao X., Sun G., Zhang D., RA Abe M., Hagiwara Y., Takahashi K., Hino O.; RT "Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel RT Fnip1-like (FnipL/Fnip2) protein."; RL Oncogene 27:5339-5347(2008). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [16] RP INVOLVEMENT IN PSP. RX PubMed=19483054; DOI=10.1183/09031936.00062608; RA Sundaram S., Tasker A.D., Morrell N.W.; RT "Familial spontaneous pneumothorax and lung cysts due to a Folliculin exon RT 10 mutation."; RL Eur. Respir. J. 33:1510-1512(2009). RN [17] RP FUNCTION. RX PubMed=21209915; DOI=10.1371/journal.pone.0015793; RA Hong S.B., Oh H., Valera V.A., Baba M., Schmidt L.S., Linehan W.M.; RT "Inactivation of the FLCN tumor suppressor gene induces TFE3 RT transcriptional activity by increasing its nuclear localization."; RL PLoS ONE 5:E15793-E15793(2010). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [19] RP SUBCELLULAR LOCATION, AND INVOLVEMENT IN BHD1. RX PubMed=23784378; DOI=10.1093/hmg/ddt288; RA Luijten M.N., Basten S.G., Claessens T., Vernooij M., Scott C.L., RA Janssen R., Easton J.A., Kamps M.A., Vreeburg M., Broers J.L., van Geel M., RA Menko F.H., Harbottle R.P., Nookala R.K., Tee A.R., Land S.C., Giles R.H., RA Coull B.J., van Steensel M.A.; RT "Birt-Hogg-Dube syndrome is a novel ciliopathy."; RL Hum. Mol. Genet. 22:4383-4397(2013). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62; SER-73; SER-302 AND RP SER-571, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [21] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24081491; DOI=10.1083/jcb.201307084; RA Petit C.S., Roczniak-Ferguson A., Ferguson S.M.; RT "Recruitment of folliculin to lysosomes supports the amino acid-dependent RT activation of Rag GTPases."; RL J. Cell Biol. 202:1107-1122(2013). RN [22] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24095279; DOI=10.1016/j.molcel.2013.09.016; RA Tsun Z.Y., Bar-Peled L., Chantranupong L., Zoncu R., Wang T., Kim C., RA Spooner E., Sabatini D.M.; RT "The folliculin tumor suppressor is a GAP for the RagC/D GTPases that RT signal amino acid levels to mTORC1."; RL Mol. Cell 52:495-505(2013). RN [23] RP INVOLVEMENT IN RCC. RX PubMed=23922894; DOI=10.1371/journal.pone.0070030; RA Bastola P., Stratton Y., Kellner E., Mikhaylova O., Yi Y., Sartor M.A., RA Medvedovic M., Biesiada J., Meller J., Czyzyk-Krzeska M.F.; RT "Folliculin contributes to VHL tumor suppressing activity in renal cancer RT through regulation of autophagy."; RL PLoS ONE 8:E70030-E70030(2013). RN [24] RP FUNCTION, INTERACTION WITH GABARAP; FNIP1 AND FNIP2, PHOSPHORYLATION AT RP SER-406; SER-537 AND SER-542, AND MUTAGENESIS OF SER-406; SER-537 AND RP SER-542. RX PubMed=25126726; DOI=10.4161/auto.29640; RA Dunlop E.A., Seifan S., Claessens T., Behrends C., Kamps M.A., Rozycka E., RA Kemp A.J., Nookala R.K., Blenis J., Coull B.J., Murray J.T., RA van Steensel M.A., Wilkinson S., Tee A.R.; RT "FLCN, a novel autophagy component, interacts with GABARAP and is regulated RT by ULK1 phosphorylation."; RL Autophagy 10:1749-1760(2014). RN [25] RP FUNCTION. RX PubMed=24448649; DOI=10.1126/scisignal.2004754; RA Martina J.A., Diab H.I., Lishu L., Jeong-A L., Patange S., Raben N., RA Puertollano R.; RT "The nutrient-responsive transcription factor TFE3 promotes autophagy, RT lysosomal biogenesis, and clearance of cellular debris."; RL Sci. Signal. 7:ra9-ra9(2014). RN [26] RP INVOLVEMENT IN PSP. RX PubMed=25827758; DOI=10.1007/s00408-015-9723-9; RA Ray A., Paul S., Chattopadhyay E., Kundu S., Roy B.; RT "Genetic analysis of familial spontaneous pneumothorax in an Indian RT family."; RL Lung 193:433-438(2015). RN [27] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RILP. RX PubMed=27113757; DOI=10.15252/embr.201541382; RA Starling G.P., Yip Y.Y., Sanger A., Morton P.E., Eden E.R., Dodding M.P.; RT "Folliculin directs the formation of a Rab34-RILP complex to control the RT nutrient-dependent dynamic distribution of lysosomes."; RL EMBO Rep. 17:823-841(2016). RN [28] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH KIF3A AND KIF3B. RX PubMed=27072130; DOI=10.1074/jbc.m116.719997; RA Zhong M., Zhao X., Li J., Yuan W., Yan G., Tong M., Guo S., Zhu Y., RA Jiang Y., Liu Y., Jiang Y.; RT "Tumor suppressor folliculin regulates mTORC1 through primary cilia."; RL J. Biol. Chem. 291:11689-11697(2016). RN [29] RP INTERACTION WITH HSP70; HSP90AA1; STUB1; CDC37; AHSA1; CCT2; STIP1; FNIP1; RP FNIP2; PTGES3 AND PPP5C. RX PubMed=27353360; DOI=10.1038/ncomms12037; RA Woodford M.R., Dunn D.M., Blanden A.R., Capriotti D., Loiselle D., RA Prodromou C., Panaretou B., Hughes P.F., Smith A., Ackerman W., RA Haystead T.A., Loh S.N., Bourboulia D., Schmidt L.S., Marston Linehan W., RA Bratslavsky G., Mollapour M.; RT "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance RT drug binding."; RL Nat. Commun. 7:12037-12037(2016). RN [30] RP SUBCELLULAR LOCATION. RX PubMed=29848618; DOI=10.1083/jcb.201712177; RA Meng J., Ferguson S.M.; RT "GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag RT GTPase heterodimer nucleotide status in response to amino acids."; RL J. Cell Biol. 217:2765-2776(2018). RN [31] RP FUNCTION. RX PubMed=31272105; DOI=10.1093/hmg/ddz158; RA Kennedy J.C., Khabibullin D., Hougard T., Nijmeh J., Shi W., Henske E.P.; RT "Loss of FLCN inhibits canonical WNT signaling via TFE3."; RL Hum. Mol. Genet. 28:3270-3281(2019). RN [32] RP FUNCTION. RX PubMed=30733432; DOI=10.1038/s41467-018-08020-0; RA Mathieu J., Detraux D., Kuppers D., Wang Y., Cavanaugh C., Sidhu S., RA Levy S., Robitaille A.M., Ferreccio A., Bottorff T., McAlister A., RA Somasundaram L., Artoni F., Battle S., Hawkins R.D., Moon R.T., Ware C.B., RA Paddison P.J., Ruohola-Baker H.; RT "Folliculin regulates mTORC1/2 and WNT pathways in early human RT pluripotency."; RL Nat. Commun. 10:632-632(2019). RN [33] RP FUNCTION. RX PubMed=32612235; DOI=10.1038/s41586-020-2444-0; RA Napolitano G., Di Malta C., Esposito A., de Araujo M.E.G., Pece S., RA Bertalot G., Matarese M., Benedetti V., Zampelli A., Stasyk T., RA Siciliano D., Venuta A., Cesana M., Vilardo C., Nusco E., Monfregola J., RA Calcagni A., Di Fiore P.P., Huber L.A., Ballabio A.; RT "A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dube syndrome."; RL Nature 585:597-602(2020). RN [34] RP FUNCTION, AND INTERACTION WITH LDHA. RX PubMed=34381247; DOI=10.1038/s41594-021-00633-2; RA Woodford M.R., Baker-Williams A.J., Sager R.A., Backe S.J., Blanden A.R., RA Hashmi F., Kancherla P., Gori A., Loiselle D.R., Castelli M., RA Serapian S.A., Colombo G., Haystead T.A., Jensen S.M., RA Stetler-Stevenson W.G., Loh S.N., Schmidt L.S., Linehan W.M., Bah A., RA Bourboulia D., Bratslavsky G., Mollapour M.; RT "The tumor suppressor folliculin inhibits lactate dehydrogenase A and RT regulates the Warburg effect."; RL Nat. Struct. Mol. Biol. 28:662-670(2021). RN [35] RP FUNCTION, AND INTERACTION WITH GABARAP. RX PubMed=34597140; DOI=10.1126/sciadv.abj2485; RA Goodwin J.M., Walkup W.G. IV, Hooper K., Li T., Kishi-Itakura C., Ng A., RA Lehmberg T., Jha A., Kommineni S., Fletcher K., Garcia-Fortanet J., Fan Y., RA Tang Q., Wei M., Agrawal A., Budhe S.R., Rouduri S.R., Baird D., RA Saunders J., Kiselar J., Chance M.R., Ballabio A., Appleton B.A., RA Brumell J.H., Florey O., Murphy L.O.; RT "GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple RT autophagy with lysosomal biogenesis."; RL Sci. Adv. 7:eabj2485-eabj2485(2021). RN [36] RP FUNCTION. RX PubMed=37079666; DOI=10.1126/science.abj5559; RA Malik N., Ferreira B.I., Hollstein P.E., Curtis S.D., Trefts E., RA Weiser Novak S., Yu J., Gilson R., Hellberg K., Fang L., Sheridan A., RA Hah N., Shadel G.S., Manor U., Shaw R.J.; RT "Induction of lysosomal and mitochondrial biogenesis by AMPK RT phosphorylation of FNIP1."; RL Science 380:eabj5559-eabj5559(2023). RN [37] RP FUNCTION. RX PubMed=39423796; DOI=10.1016/j.molcel.2024.08.026; RA Lv B., Dion W.A., Yang H., Xun J., Kim D.H., Zhu B., Tan J.X.; RT "A TBK1-independent primordial function of STING in lysosomal biogenesis."; RL Mol. Cell 84:3979-3996(2024). RN [38] {ECO:0007744|PDB:3V42} RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 341-566. RX PubMed=22977732; DOI=10.1098/rsob.120071; RA Nookala R.K., Langemeyer L., Pacitto A., Ochoa-Montano B., Donaldson J.C., RA Blaszczyk B.K., Chirgadze D.Y., Barr F.A., Bazan J.F., Blundell T.L.; RT "Crystal structure of folliculin reveals a hidDENN function in genetically RT inherited renal cancer."; RL Open Biol. 2:120071-120071(2012). RN [39] {ECO:0007744|PDB:6ULG} RP STRUCTURE BY ELECTRON MICROSCOPY (3.31 ANGSTROMS) IN COMPLEX WITH FNIP2; RP RRAGA; RRAGC; LAMTOR1; LAMTOR2; LAMTOR3; LAMTOR4 AND LAMTOR5, FUNCTION, RP IDENTIFICATION IN THE LFC COMPLEX, AND MUTAGENESIS OF ARG-164. RX PubMed=31704029; DOI=10.1016/j.cell.2019.10.036; RA Shen K., Rogala K.B., Chou H.T., Huang R.K., Yu Z., Sabatini D.M.; RT "Cryo-EM structure of the human FLCN-FNIP2-Rag-Ragulator complex."; RL Cell 179:1319-1329(2019). RN [40] {ECO:0007744|PDB:6NZD} RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) IN COMPLEX WITH FNIP2; RP RRAGA; RRAGC; LAMTOR1; LAMTOR2; LAMTOR3; LAMTOR4 AND LAMTOR5, FUNCTION, RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, IDENTIFICATION IN THE LFC RP COMPLEX, AND MUTAGENESIS OF PHE-118 AND ARG-164. RX PubMed=31672913; DOI=10.1126/science.aax0364; RA Lawrence R.E., Fromm S.A., Fu Y., Yokom A.L., Kim D.J., Thelen A.M., RA Young L.N., Lim C.Y., Samelson A.J., Hurley J.H., Zoncu R.; RT "Structural mechanism of a Rag GTPase activation checkpoint by the RT lysosomal folliculin complex."; RL Science 366:971-977(2019). RN [41] {ECO:0007744|PDB:8DHB} RP STRUCTURE BY ELECTRON MICROSCOPY (3.53 ANGSTROMS) IN COMPLEX WITH RRAGA; RP RRAGC; LAMTOR1; LAMTOR2; LAMTOR3; LAMTOR4; LAMTOR5; FNIP2 AND SLC38A9, RP FUNCTION, INTERACTION WITH FNIP2, AND MUTAGENESIS OF PHE-10. RX PubMed=36103527; DOI=10.1126/sciadv.add2926; RA Jansen R.M., Peruzzo R., Fromm S.A., Yokom A.L., Zoncu R., Hurley J.H.; RT "Structural basis for FLCN RagC GAP activation in MiT-TFE substrate- RT selective mTORC1 regulation."; RL Sci. Adv. 8:eadd2926-eadd2926(2022). RN [42] RP VARIANTS PSP 315-GLU--ASN-579 DEL AND 477-ARG--ASN-579 DEL. RX PubMed=15805188; DOI=10.1164/rccm.200501-143oc; RA Graham R.B., Nolasco M., Peterlin B., Garcia C.K.; RT "Nonsense mutations in folliculin presenting as isolated familial RT spontaneous pneumothorax in adults."; RL Am. J. Respir. Crit. Care Med. 172:39-44(2005). RN [43] RP VARIANT RCC CYS-239. RX PubMed=18794106; DOI=10.1158/1078-0432.ccr-08-0608; RA Woodward E.R., Ricketts C., Killick P., Gad S., Morris M.R., Kavalier F., RA Hodgson S.V., Giraud S., Bressac-de Paillerets B., Chapman C., Escudier B., RA Latif F., Richard S., Maher E.R.; RT "Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical RT features, segregation analysis, and mutation analysis of FLCN."; RL Clin. Cancer Res. 14:5925-5930(2008). RN [44] RP VARIANTS PSP PHE-157 DEL AND TYR-429. RX PubMed=18505456; DOI=10.1111/j.1399-0004.2008.01030.x; RA Ren H.Z., Zhu C.C., Yang C., Chen S.L., Xie J., Hou Y.Y., Xu Z.F., RA Wang D.J., Mu D.K., Ma D.H., Wang Y., Ye M.H., Ye Z.R., Chen B.F., RA Wang C.G., Lin J., Qiao D., Yi L.; RT "Mutation analysis of the FLCN gene in Chinese patients with sporadic and RT familial isolated primary spontaneous pneumothorax."; RL Clin. Genet. 74:178-183(2008). RN [45] RP VARIANT PSP LYS-132. RX PubMed=18579543; DOI=10.1183/09031936.00132707; RA Frohlich B.A., Zeitz C., Matyas G., Alkadhi H., Tuor C., Berger W., RA Russi E.W.; RT "Novel mutations in the folliculin gene associated with spontaneous RT pneumothorax."; RL Eur. Respir. J. 32:1316-1320(2008). RN [46] RP VARIANT BHD1 ARG-508. RX PubMed=18234728; DOI=10.1136/jmg.2007.054304; RA Toro J.R., Wei M.H., Glenn G.M., Weinreich M., Toure O., Vocke C., RA Turner M., Choyke P., Merino M.J., Pinto P.A., Steinberg S.M., RA Schmidt L.S., Linehan W.M.; RT "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg- RT Dube syndrome: a new series of 50 families and a review of published RT reports."; RL J. Med. Genet. 45:321-331(2008). RN [47] RP VARIANT BHD1 ILE-108. RX PubMed=19785621; DOI=10.1111/j.1365-2133.2009.09517.x; RA Kluger N., Giraud S., Coupier I., Avril M.F., Dereure O., Guillot B., RA Richard S., Bessis D.; RT "Birt-Hogg-Dube syndrome: clinical and genetic studies of 10 French RT families."; RL Br. J. Dermatol. 162:527-537(2010). RN [48] RP VARIANT CYS-362, AND CHARACTERIZATION OF VARIANTS PHE-157 DEL; CYS-239; RP CYS-362 AND ARG-508. RX PubMed=21538689; DOI=10.1002/humu.21519; RA Nahorski M.S., Reiman A., Lim D.H., Nookala R.K., Seabra L., Lu X., RA Fenton J., Boora U., Nordenskjold M., Latif F., Hurst L.D., Maher E.R.; RT "Birt Hogg-Dube syndrome-associated FLCN mutations disrupt protein RT stability."; RL Hum. Mutat. 32:921-929(2011). RN [49] RP VARIANT PSP 170-TYR--ASN-579 DEL. RX PubMed=27486260; DOI=10.1093/qjmed/hcw109; RA Zhu J.F., Shen X.Q., Zhu F., Tian L.; RT "Novel folliculin (FLCN) mutation and familial spontaneous pneumothorax."; RL QJM 110:23-26(2017). RN [50] RP VARIANT PSP 425-GLN--ASN-579 DEL. RX PubMed=31625278; DOI=10.1002/mgg3.1003; RA Genc Yavuz B., Guzel Tanoglu E., Salman Yilmaz S., Colak S.; RT "A novel FLCN mutation in family members diagnosed with primary spontaneous RT pneumothorax."; RL Mol. Genet. Genomic Med. 7:E1003-E1003(2019). RN [51] RP VARIANTS BHD1 PHE-157 DEL; 220-GLN--ASN-579 DEL; 339-GLN--ASN-579 DEL; RP 409-TYR--ASN-579 DEL; 511-TRP--ASN-579 DEL AND 533-GLN--ASN-579 DEL. RX PubMed=31615547; DOI=10.1186/s13023-019-1198-y; RA Liu K., Xu W., Tian X., Xiao M., Zhao X., Zhang Q., Qu T., Song J., Liu Y., RA Xu K.F., Zhang X.; RT "Genotypic characteristics of Chinese patients with BHD syndrome and RT functional analysis of FLCN variants."; RL Orphanet J. Rare Dis. 14:223-223(2019). CC -!- FUNCTION: Multi-functional protein, involved in both the cellular CC response to amino acid availability and in the regulation of glycolysis CC (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, CC PubMed:24095279, PubMed:31672913, PubMed:31704029, PubMed:32612235, CC PubMed:34381247, PubMed:36103527, PubMed:37079666). GTPase-activating CC protein that plays a key role in the cellular response to amino acid CC availability through regulation of the non-canonical mTORC1 signaling CC cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, CC PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, CC PubMed:24448649, PubMed:31672913, PubMed:31704029, PubMed:32612235, CC PubMed:36103527, PubMed:37079666). Activates mTORC1 by acting as a CC GTPase-activating protein: specifically stimulates GTP hydrolysis by CC RagC/RRAGC or RagD/RRAGD, promoting the conversion to the GDP-bound CC state of RagC/RRAGC or RagD/RRAGD, and thereby activating the kinase CC activity of mTORC1 (PubMed:24095279, PubMed:31672913, PubMed:31704029, CC PubMed:32612235, PubMed:37079666). The GTPase-activating activity is CC inhibited during starvation and activated in presence of nutrients CC (PubMed:31672913, PubMed:32612235). Acts as a key component for non- CC canonical mTORC1-dependent control of the MiT/TFE factors TFEB and CC TFE3, while it is not involved in mTORC1-dependent phosphorylation of CC canonical RPS6KB1/S6K1 and EIF4EBP1/4E-BP1 (PubMed:21209915, CC PubMed:24081491, PubMed:31672913, PubMed:32612235). In low-amino acid CC conditions, the lysosomal folliculin complex (LFC) is formed on the CC membrane of lysosomes, which inhibits the GTPase-activating activity of CC FLCN, inactivates mTORC1 and maximizes nuclear translocation of TFEB CC and TFE3 (PubMed:31672913). Upon amino acid restimulation, RagA/RRAGA CC (or RagB/RRAGB) nucleotide exchange promotes disassembly of the LFC CC complex and liberates the GTPase-activating activity of FLCN, leading CC to activation of mTORC1 and subsequent cytoplasmic retention of TFEB CC and TFE3 (PubMed:31672913). Indirectly acts as a positive regulator of CC Wnt signaling by promoting mTOR-dependent cytoplasmic retention of CC MiT/TFE factor TFE3 (PubMed:31272105). Required for the exit of CC hematopoietic stem cell from pluripotency by promoting mTOR-dependent CC cytoplasmic retention of TFE3, thereby increasing Wnt signaling CC (PubMed:30733432). Acts as an inhibitor of browning of adipose tissue CC by regulating mTOR-dependent cytoplasmic retention of TFE3 (By CC similarity). Involved in the control of embryonic stem cells CC differentiation; together with LAMTOR1 it is necessary to recruit and CC activate RagC/RRAGC and RagD/RRAGD at the lysosomes, and to induce exit CC of embryonic stem cells from pluripotency via non-canonical, mTOR- CC independent TFE3 inactivation (By similarity). In response to flow CC stress, regulates STK11/LKB1 accumulation and mTORC1 activation through CC primary cilia: may act by recruiting STK11/LKB1 to primary cilia for CC activation of AMPK resided at basal bodies, causing mTORC1 down- CC regulation (PubMed:27072130). Together with FNIP1 and/or FNIP2, CC regulates autophagy: following phosphorylation by ULK1, interacts with CC GABARAP and promotes autophagy (PubMed:25126726). Interaction with CC GABARAP also inhibits the non-canonical mTORC1 signaling cascade: CC GABARAP sequesters FLCN, thereby inactivating mTORC1 and promoting CC nuclear translocation of TFEB and TFE3 (PubMed:34597140, CC PubMed:39423796). Required for starvation-induced perinuclear CC clustering of lysosomes by promoting association of RILP with its CC effector RAB34 (PubMed:27113757). Regulates glycolysis by binding to CC lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor CC (PubMed:34381247). {ECO:0000250|UniProtKB:Q8QZS3, CC ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353, CC ECO:0000269|PubMed:21209915, ECO:0000269|PubMed:24081491, CC ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:24448649, CC ECO:0000269|PubMed:25126726, ECO:0000269|PubMed:27072130, CC ECO:0000269|PubMed:27113757, ECO:0000269|PubMed:30733432, CC ECO:0000269|PubMed:31272105, ECO:0000269|PubMed:31672913, CC ECO:0000269|PubMed:31704029, ECO:0000269|PubMed:32612235, CC ECO:0000269|PubMed:34381247, ECO:0000269|PubMed:34597140, CC ECO:0000269|PubMed:36103527, ECO:0000269|PubMed:37079666, CC ECO:0000269|PubMed:39423796}. CC -!- ACTIVITY REGULATION: GTPase-activating activity is inhibited in the CC folliculin complex (LFC), which stabilizes the GDP-bound state of CC RagA/RRAGA (or RagB/RRAGB), because Arg-164 is located far from the CC RagC/RRAGC or RagD/RRAGD nucleotide pocket (PubMed:31672913). CC Disassembly of the LFC complex upon amino acid restimulation liberates CC the GTPase-activating activity (PubMed:31672913). CC {ECO:0000269|PubMed:31672913}. CC -!- SUBUNIT: Interacts (via C-terminus) with FNIP1 or FNIP2 (via C- CC terminus) (PubMed:17028174, PubMed:18403135, PubMed:18663353, CC PubMed:27353360, PubMed:36103527). Component of the lysosomal CC folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), CC RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, CC and Ragulator (PubMed:31672913, PubMed:31704029, PubMed:36103527). CC Interaction with FNIP1 or FNIP2 mediates indirect interaction with the CC PRKAA1, PRKAB1 and PRKAG1 subunits of 5'-AMP-activated protein kinase CC (AMPK) (PubMed:17028174). Interacts with HSP90AA1 in the presence of CC FNIP1 (PubMed:27353360). Interacts with HSP70, STUB1, CDC37, AHSA1, CC CCT2, STIP1, PTGES3 and PPP5C (PubMed:27353360). Interacts with CC GABARAP; interaction takes place in the presence of FNIP1 and/or FNIP2 CC (PubMed:25126726). Interaction with GABARAP sequesters FLCN, thereby CC inactivating mTORC1 (PubMed:34597140). Interacts with RILP; the CC interaction is direct and promotes association between RILP and RAB34 CC (PubMed:27113757). Interacts with KIF3A and KIF3B (PubMed:27072130). CC Interacts with lactate dehydrogenase LDHA, but not LDHB; the CC interaction is direct, may preferentially bind LDHA dimers rather than CC tetramers, and regulates LDHA activity, acting as an uncompetitive CC inhibitor (PubMed:34381247). {ECO:0000269|PubMed:17028174, CC ECO:0000269|PubMed:18403135, ECO:0000269|PubMed:18663353, CC ECO:0000269|PubMed:25126726, ECO:0000269|PubMed:27072130, CC ECO:0000269|PubMed:27113757, ECO:0000269|PubMed:27353360, CC ECO:0000269|PubMed:31672913, ECO:0000269|PubMed:31704029, CC ECO:0000269|PubMed:34381247, ECO:0000269|PubMed:34597140, CC ECO:0000269|PubMed:36103527}. CC -!- INTERACTION: CC Q8NFG4; Q8TF40: FNIP1; NbExp=5; IntAct=EBI-2970160, EBI-2946919; CC Q8NFG4; Q9P278: FNIP2; NbExp=7; IntAct=EBI-2970160, EBI-7597109; CC Q8NFG4-1; Q8TF40-1: FNIP1; NbExp=7; IntAct=EBI-15604776, EBI-15604805; CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:24081491, CC ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:27113757, CC ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}. Cytoplasm, CC cytosol {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353, CC ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:24095279, CC ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}. Cell CC projection, cilium {ECO:0000269|PubMed:23784378, CC ECO:0000269|PubMed:27072130}. Cytoplasm, cytoskeleton, microtubule CC organizing center, centrosome {ECO:0000269|PubMed:23784378}. Cytoplasm, CC cytoskeleton, spindle {ECO:0000269|PubMed:23784378}. Nucleus CC {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353}. CC Note=Localizes to lysosome membrane in amino acid-depleted conditions CC and relocalizes to the cytosol upon refeeding (PubMed:24095279, CC PubMed:29848618, PubMed:31672913). Colocalizes with FNIP1 and FNIP2 in CC the cytoplasm (PubMed:17028174, PubMed:18663353). Also localizes to CC motile and non-motile cilia, centrosomes and the mitotic spindle CC (PubMed:23784378). {ECO:0000269|PubMed:17028174, CC ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:23784378, CC ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:29848618, CC ECO:0000269|PubMed:31672913}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q8NFG4-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8NFG4-2; Sequence=VSP_017314, VSP_017315; CC Name=3; CC IsoId=Q8NFG4-3; Sequence=VSP_017312, VSP_017313; CC -!- TISSUE SPECIFICITY: Expressed in most tissues tested, including skin, CC lung, kidney, heart, testis and stomach. {ECO:0000269|PubMed:12204536}. CC -!- DEVELOPMENTAL STAGE: Expressed in fetal lung, kidney, liver, and brain. CC {ECO:0000269|PubMed:12204536}. CC -!- PTM: Phosphorylation by ULK1 modulates the interaction with GABARAP and CC is required to regulate autophagy. {ECO:0000269|PubMed:25126726}. CC -!- DISEASE: Birt-Hogg-Dube syndrome 1 (BHD1) [MIM:135150]: A form of Birt- CC Hogg-Dube syndrome, a rare genodermatosis usually manifesting in CC adulthood and characterized by multiple fibrofolliculomas, CC trichodiscomas, and acrochordons. Patients with this syndrome have an CC increased susceptibility to develop renal cell carcinoma, lung cysts, CC and spontaneous pneumothorax. Inheritance is autosomal dominant. CC {ECO:0000269|PubMed:12204536, ECO:0000269|PubMed:15852235, CC ECO:0000269|PubMed:18234728, ECO:0000269|PubMed:19785621, CC ECO:0000269|PubMed:23784378, ECO:0000269|PubMed:31615547}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Primary spontaneous pneumothorax (PSP) [MIM:173600]: Condition CC in which air is present in the pleural space in the absence of a CC precipitating event, such as trauma or lung disease. This results in CC secondary collapse of the lung, either partially or completely, and CC some degree of hypoxia. PSP is relatively common, with an incidence CC between 7.4-18/100'000 for men and 1.2-6/100'000 for women and a dose- CC dependent, increased risk among smokers. Most cases are sporadic, CC typically occurring in tall, thin men aged 10-30 years and generally CC while at rest. Familial PSP is rarer and usually is inherited as an CC autosomal dominant condition with reduced penetrance, although X-linked CC recessive and autosomal recessive inheritance have also been suggested. CC {ECO:0000269|PubMed:15657874, ECO:0000269|PubMed:15805188, CC ECO:0000269|PubMed:17496196, ECO:0000269|PubMed:18505456, CC ECO:0000269|PubMed:18579543, ECO:0000269|PubMed:19483054, CC ECO:0000269|PubMed:25827758, ECO:0000269|PubMed:27486260, CC ECO:0000269|PubMed:31625278}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma CC is a heterogeneous group of sporadic or hereditary carcinoma derived CC from cells of the proximal renal tubular epithelium. It is CC subclassified into clear cell renal carcinoma (non-papillary CC carcinoma), papillary renal cell carcinoma, chromophobe renal cell CC carcinoma, collecting duct carcinoma with medullary carcinoma of the CC kidney, and unclassified renal cell carcinoma. Clear cell renal cell CC carcinoma is the most common subtype. {ECO:0000269|PubMed:18794106, CC ECO:0000269|PubMed:23922894}. Note=The gene represented in this entry CC may be involved in disease pathogenesis. CC -!- SIMILARITY: Belongs to the folliculin family. {ECO:0000305}. CC -!- CAUTION: Based on its structure and in vitro assays, was initially CC thought to have guanine nucleotide exchange factor (GEF) activity CC (PubMed:22977732). However, subsequent studies showed that it does not CC act as GEF in vivo (PubMed:24095279). {ECO:0000269|PubMed:22977732, CC ECO:0000269|PubMed:24095279}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/789/FLCN"; CC -!- WEB RESOURCE: Name=Leiden Open Variation Database; Note=Folliculin CC (FLCN); CC URL="https://databases.lovd.nl/shared/genes/FLCN"; 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; AF517523; AAM94803.1; -; mRNA. DR EMBL; AK127912; BAC87186.1; -; mRNA. DR EMBL; AK126951; BAC86760.1; -; mRNA. DR EMBL; AC055811; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471196; EAW55716.1; -; Genomic_DNA. DR EMBL; BC015687; AAH15687.1; -; mRNA. DR EMBL; BC015725; AAH15725.2; -; mRNA. DR CCDS; CCDS32579.1; -. [Q8NFG4-1] DR CCDS; CCDS32580.1; -. [Q8NFG4-2] DR RefSeq; NP_001340159.1; NM_001353230.2. [Q8NFG4-1] DR RefSeq; NP_001340160.1; NM_001353231.2. [Q8NFG4-1] DR RefSeq; NP_653207.1; NM_144606.7. [Q8NFG4-2] DR RefSeq; NP_659434.2; NM_144997.7. [Q8NFG4-1] DR RefSeq; XP_016879797.1; XM_017024308.2. [Q8NFG4-1] DR RefSeq; XP_047291491.1; XM_047435535.1. [Q8NFG4-1] DR RefSeq; XP_047291492.1; XM_047435536.1. [Q8NFG4-1] DR RefSeq; XP_047291493.1; XM_047435537.1. [Q8NFG4-1] DR RefSeq; XP_047291494.1; XM_047435538.1. [Q8NFG4-1] DR RefSeq; XP_054171315.1; XM_054315340.1. [Q8NFG4-1] DR RefSeq; XP_054171316.1; XM_054315341.1. [Q8NFG4-1] DR RefSeq; XP_054171317.1; XM_054315342.1. [Q8NFG4-1] DR RefSeq; XP_054171318.1; XM_054315343.1. [Q8NFG4-1] DR RefSeq; XP_054171319.1; XM_054315344.1. [Q8NFG4-1] DR PDB; 3V42; X-ray; 2.00 A; A/B=341-566. DR PDB; 6NZD; EM; 3.60 A; H=1-579. DR PDB; 6ULG; EM; 3.31 A; L=1-579. DR PDB; 8DHB; EM; 3.53 A; J=1-579. DR AlphaFoldDB; Q8NFG4; -. DR EMDB; EMD-0554; -. DR EMDB; EMD-20814; -. DR EMDB; EMD-27435; -. DR SMR; Q8NFG4; -. DR BioGRID; 128366; 106. DR ComplexPortal; CPX-2440; FLCN-FNIP GTPase-activating complex, FNIP2 variant. DR ComplexPortal; CPX-2624; FLCN-FNIP GTPase-activating complex, FNIP1 variant. DR CORUM; Q8NFG4; -. DR DIP; DIP-61287N; -. DR FunCoup; Q8NFG4; 2290. DR IntAct; Q8NFG4; 59. DR MINT; Q8NFG4; -. DR NDEx; IQUERY-CP-FLCN; 4 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000285071; -. DR GlyGen; Q8NFG4; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q8NFG4; -. DR MetOSite; Q8NFG4; -. DR PhosphoSitePlus; Q8NFG4; -. DR BioMuta; FLCN; -. DR DMDM; 74751276; -. DR jPOST; Q8NFG4; -. DR MassIVE; Q8NFG4; -. DR PaxDb; 9606-ENSP00000285071; -. DR PeptideAtlas; Q8NFG4; -. DR ProteomicsDB; 73302; -. [Q8NFG4-1] DR ProteomicsDB; 73303; -. [Q8NFG4-2] DR ProteomicsDB; 73304; -. [Q8NFG4-3] DR Pumba; Q8NFG4; -. DR Antibodypedia; 4192; 317 antibodies from 38 providers. DR DNASU; 201163; -. DR Ensembl; ENST00000285071.9; ENSP00000285071.4; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000389169.9; ENSP00000373821.5; ENSG00000154803.14. [Q8NFG4-2] DR Ensembl; ENST00000888043.1; ENSP00000558102.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000888044.1; ENSP00000558103.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000888045.1; ENSP00000558104.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000918780.1; ENSP00000588839.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000918781.1; ENSP00000588840.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000962727.1; ENSP00000632786.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000962728.1; ENSP00000632787.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000962731.1; ENSP00000632790.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000962732.1; ENSP00000632791.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000962737.1; ENSP00000632796.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000962738.1; ENSP00000632797.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000962739.1; ENSP00000632798.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000962745.1; ENSP00000632804.1; ENSG00000154803.14. [Q8NFG4-1] DR Ensembl; ENST00000962746.1; ENSP00000632805.1; ENSG00000154803.14. [Q8NFG4-1] DR GeneID; 201163; -. DR KEGG; hsa:201163; -. DR MANE-Select; ENST00000285071.9; ENSP00000285071.4; NM_144997.7; NP_659434.2. DR UCSC; uc002gra.5; human. [Q8NFG4-1] DR AGR; HGNC:27310; -. DR ClinPGx; PA134901005; -. DR CTD; 201163; -. DR DisGeNET; 201163; -. DR GeneCards; FLCN; -. DR GeneReviews; FLCN; -. DR HGNC; HGNC:27310; FLCN. DR HPA; ENSG00000154803; Low tissue specificity. DR MalaCards; FLCN; -. DR MIM; 135150; phenotype. DR MIM; 144700; phenotype. DR MIM; 173600; phenotype. DR MIM; 607273; gene. DR OpenTargets; ENSG00000154803; -. DR Orphanet; 122; Birt-Hogg-Dube syndrome. DR Orphanet; 2903; Familial spontaneous pneumothorax. DR Orphanet; 422526; Hereditary clear cell renal cell carcinoma. DR VEuPathDB; HostDB:ENSG00000154803; -. DR eggNOG; KOG3715; Eukaryota. DR GeneTree; ENSGT00390000009864; -. DR HOGENOM; CLU_035854_2_0_1; -. DR InParanoid; Q8NFG4; -. DR OMA; LWASLHC; -. DR OrthoDB; 5599713at2759; -. DR PAN-GO; Q8NFG4; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q8NFG4; -. DR PathwayCommons; Q8NFG4; -. DR Reactome; R-HSA-9639288; Amino acids regulate mTORC1. DR SignaLink; Q8NFG4; -. DR SIGNOR; Q8NFG4; -. DR Agora; ENSG00000154803; -. DR BioGRID-ORCS; 201163; 92 hits in 1159 CRISPR screens. DR ChiTaRS; FLCN; human. DR EvolutionaryTrace; Q8NFG4; -. DR GeneWiki; Folliculin; -. DR GenomeRNAi; 201163; -. DR Pharos; Q8NFG4; Tbio. DR PRO; PR:Q8NFG4; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q8NFG4; protein. DR Bgee; ENSG00000154803; Expressed in buccal mucosa cell and 181 other cell types or tissues. DR ExpressionAtlas; Q8NFG4; baseline and differential. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0005929; C:cilium; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:1990877; C:FNIP-folliculin RagC/D GAP; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; TAS:ParkinsonsUK-UCL. DR GO; GO:0072686; C:mitotic spindle; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0004857; F:enzyme inhibitor activity; IDA:UniProtKB. DR GO; GO:0005096; F:GTPase activator activity; IDA:UniProtKB. DR GO; GO:0007043; P:cell-cell junction assembly; ISS:UniProtKB. DR GO; GO:0034198; P:cellular response to amino acid starvation; IDA:UniProtKB. DR GO; GO:0009267; P:cellular response to starvation; IDA:UniProtKB. DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB. DR GO; GO:0030097; P:hemopoiesis; ISS:UniProtKB. DR GO; GO:0001701; P:in utero embryonic development; ISS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0032418; P:lysosome localization; IDA:UniProtKB. DR GO; GO:1903444; P:negative regulation of brown fat cell differentiation; ISS:UniProtKB. DR GO; GO:1901723; P:negative regulation of cell proliferation involved in kidney development; ISS:UniProtKB. DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:UniProtKB. DR GO; GO:0045820; P:negative regulation of glycolytic process; IDA:UniProtKB. DR GO; GO:1905672; P:negative regulation of lysosome organization; IDA:UniProtKB. DR GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:UniProtKB. DR GO; GO:1901874; P:negative regulation of post-translational protein modification; IEA:Ensembl. DR GO; GO:0035024; P:negative regulation of Rho protein signal transduction; IMP:UniProtKB. DR GO; GO:0032007; P:negative regulation of TOR signaling; ISS:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProtKB. DR GO; GO:0032008; P:positive regulation of TOR signaling; IDA:UniProtKB. DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IDA:UniProtKB. DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; ISS:UniProtKB. DR GO; GO:2000973; P:regulation of pro-B cell differentiation; ISS:UniProtKB. DR GO; GO:0046578; P:regulation of Ras protein signal transduction; IDA:UniProtKB. DR GO; GO:0032006; P:regulation of TOR signaling; ISS:UniProtKB. DR FunFam; 1.10.10.1730:FF:000001; Folliculin; 1. DR FunFam; 3.40.50.12430:FF:000001; Folliculin; 1. DR Gene3D; 3.40.50.12430; -; 1. DR Gene3D; 1.10.10.1730; Folliculin; 1. DR InterPro; IPR037521; FLCN/SMCR8_DENN. DR InterPro; IPR044886; FLCN_DENN_C_sf. DR InterPro; IPR021713; Folliculin. DR InterPro; IPR037520; Folliculin/SMCR8_longin. DR InterPro; IPR032035; Folliculin_DENN. DR PANTHER; PTHR31441:SF2; FOLLICULIN; 1. DR PANTHER; PTHR31441; FOLLICULIN FAMILY MEMBER; 1. DR Pfam; PF11704; Folliculin; 1. DR Pfam; PF16692; Folliculin_C; 1. DR PROSITE; PS51834; DENN_FLCN_SMCR8; 1. DR PDBsum; 3V42; -. DR PDBsum; 6NZD; -. DR PDBsum; 6ULG; -. DR PDBsum; 8DHB; -. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell projection; Coiled coil; KW Cytoplasm; Cytoskeleton; Disease variant; GTPase activation; Lysosome; KW Membrane; Nucleus; Phosphoprotein; Proteomics identification; KW Reference proteome; Tumor suppressor. FT CHAIN 1..579 FT /note="Folliculin" FT /id="PRO_0000223940" FT DOMAIN 86..242 FT /note="uDENN FLCN/SMCR8-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01178" FT DOMAIN 339..491 FT /note="cDENN FLCN/SMCR8-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01178" FT DOMAIN 493..558 FT /note="dDENN FLCN/SMCR8-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01178" FT REGION 30..81 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 210..220 FT /note="Essential for interaction with LDHA" FT /evidence="ECO:0000269|PubMed:34381247" FT REGION 294..337 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 287..310 FT /evidence="ECO:0000255" FT COMPBIAS 294..308 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 326..336 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 164 FT /note="Essential for GTPase activation (GAP) activity" FT /evidence="ECO:0000269|PubMed:31672913, FT ECO:0000269|PubMed:31704029" FT MOD_RES 62 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 73 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 302 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 406 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:25126726" FT MOD_RES 537 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:25126726" FT MOD_RES 542 FT /note="Phosphoserine; by ULK1" FT /evidence="ECO:0000269|PubMed:25126726" FT MOD_RES 571 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VAR_SEQ 134..197 FT /note="CPGREGPIFFGDEQHGFVFSHTFFIKDSLARGFQRWYSIITIMMDRIYLINS FT WPFLLGKVRGII -> SLVATEPVSVGAHMLPGALGGLGASIAQGGRHWSSLRADPQIS FT TAQGTGRLPCPELREESCWTC (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_017312" FT VAR_SEQ 198..579 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_017313" FT VAR_SEQ 291..342 FT /note="DLEEESESWDNSEAEEEEKAPVLPESTEGRELTQGPAESSSLSGCGSWQPRK FT -> GEAGVLLPGPWPGWPWGGTSCLLSWQESLREGNAALNQPRTSLREAHPPISV (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_017314" FT VAR_SEQ 343..579 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_017315" FT VARIANT 79 FT /note="S -> W (in a sporadic colorectal carcinoma; somatic FT mutation; dbSNP:rs137852930)" FT /evidence="ECO:0000269|PubMed:12843323" FT /id="VAR_025356" FT VARIANT 108 FT /note="S -> I (in BHD1; dbSNP:rs2145012002)" FT /evidence="ECO:0000269|PubMed:19785621" FT /id="VAR_066023" FT VARIANT 132 FT /note="E -> K (in PSP; dbSNP:rs2145009956)" FT /evidence="ECO:0000269|PubMed:18579543" FT /id="VAR_066024" FT VARIANT 157 FT /note="Missing (in PSP and BHD1; impaired protein FT stability; dbSNP:rs786203218)" FT /evidence="ECO:0000269|PubMed:18505456, FT ECO:0000269|PubMed:21538689, ECO:0000269|PubMed:31615547" FT /id="VAR_066025" FT VARIANT 170..579 FT /note="Missing (in PSP)" FT /evidence="ECO:0000269|PubMed:27486260" FT /id="VAR_083268" FT VARIANT 220..579 FT /note="Missing (in BHD1)" FT /evidence="ECO:0000269|PubMed:31615547" FT /id="VAR_083269" FT VARIANT 238 FT /note="A -> V (in a renal cell carcinoma cell line)" FT /evidence="ECO:0000269|PubMed:14627671" FT /id="VAR_025357" FT VARIANT 239 FT /note="R -> C (in RCC; impaired protein stability; FT dbSNP:rs78683075)" FT /evidence="ECO:0000269|PubMed:18794106, FT ECO:0000269|PubMed:21538689" FT /id="VAR_066026" FT VARIANT 315..579 FT /note="Missing (in PSP)" FT /evidence="ECO:0000269|PubMed:15805188" FT /id="VAR_083270" FT VARIANT 320 FT /note="R -> Q (in a primary colorectal cancer; FT dbSNP:rs143483053)" FT /evidence="ECO:0000269|PubMed:14627671" FT /id="VAR_025358" FT VARIANT 339..579 FT /note="Missing (in BHD1)" FT /evidence="ECO:0000269|PubMed:31615547" FT /id="VAR_083271" FT VARIANT 362 FT /note="R -> C (found in a colorectal cell line; impaired FT protein stability; dbSNP:rs557336321)" FT /evidence="ECO:0000269|PubMed:21538689" FT /id="VAR_066027" FT VARIANT 392 FT /note="R -> G (in a primary colorectal cancer; somatic FT mutation; dbSNP:rs1060502374)" FT /evidence="ECO:0000269|PubMed:14627671" FT /id="VAR_025359" FT VARIANT 409..579 FT /note="Missing (in BHD1)" FT /evidence="ECO:0000269|PubMed:31615547" FT /id="VAR_083272" FT VARIANT 425..579 FT /note="Missing (in PSP)" FT /evidence="ECO:0000269|PubMed:31625278" FT /id="VAR_083273" FT VARIANT 429 FT /note="H -> Y (in PSP; dbSNP:rs375082054)" FT /evidence="ECO:0000269|PubMed:18505456" FT /id="VAR_066028" FT VARIANT 444 FT /note="A -> S (in a primary clear-cell renal cell FT carcinoma; somatic mutation)" FT /evidence="ECO:0000269|PubMed:14627671" FT /id="VAR_025360" FT VARIANT 445 FT /note="A -> T (in a sporadic colorectal carcinoma; somatic FT mutation; dbSNP:rs41419545)" FT /evidence="ECO:0000269|PubMed:12843323" FT /id="VAR_025361" FT VARIANT 477..579 FT /note="Missing (in PSP)" FT /evidence="ECO:0000269|PubMed:15805188" FT /id="VAR_083274" FT VARIANT 508 FT /note="K -> R (in BHD1; does not impair protein stability, FT growth suppression activity or intracellular localization FT of folliculin; dbSNP:rs199643834)" FT /evidence="ECO:0000269|PubMed:18234728, FT ECO:0000269|PubMed:21538689" FT /id="VAR_066029" FT VARIANT 511..579 FT /note="Missing (in BHD1)" FT /evidence="ECO:0000269|PubMed:31615547" FT /id="VAR_083275" FT VARIANT 533..579 FT /note="Missing (in BHD1)" FT /evidence="ECO:0000269|PubMed:31615547" FT /id="VAR_083276" FT MUTAGEN 10 FT /note="F->D: Abolished GTPase activation (GAP) activity." FT /evidence="ECO:0000269|PubMed:36103527" FT MUTAGEN 118 FT /note="F->D: Does not assemble into a stable folliculin FT complex (LFC), preventing localization to the lysosomal FT membrane upon amino acid starvation." FT /evidence="ECO:0000269|PubMed:31672913" FT MUTAGEN 164 FT /note="R->A: Abolished GTPase activation (GAP) activity." FT /evidence="ECO:0000269|PubMed:31672913, FT ECO:0000269|PubMed:31704029" FT MUTAGEN 406 FT /note="S->A: Impaired ability to regulate autophagy; when FT associated with A-537 and A-542." FT /evidence="ECO:0000269|PubMed:25126726" FT MUTAGEN 537 FT /note="S->A: Impaired ability to regulate autophagy; when FT associated with A-406 and A-542." FT /evidence="ECO:0000269|PubMed:25126726" FT MUTAGEN 542 FT /note="S->A: Impaired ability to regulate autophagy; when FT associated with A-406 and A-537." FT /evidence="ECO:0000269|PubMed:25126726" FT STRAND 4..10 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 12..14 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 16..22 FT /evidence="ECO:0007829|PDB:6ULG" FT HELIX 92..94 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 95..99 FT /evidence="ECO:0007829|PDB:6ULG" FT TURN 100..103 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 104..108 FT /evidence="ECO:0007829|PDB:6ULG" FT HELIX 115..129 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 135..137 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 139..144 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 150..159 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 161..177 FT /evidence="ECO:0007829|PDB:6ULG" FT HELIX 179..183 FT /evidence="ECO:0007829|PDB:6ULG" FT HELIX 186..214 FT /evidence="ECO:0007829|PDB:6ULG" FT HELIX 224..226 FT /evidence="ECO:0007829|PDB:6ULG" FT TURN 241..243 FT /evidence="ECO:0007829|PDB:6ULG" FT HELIX 250..266 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 267..269 FT /evidence="ECO:0007829|PDB:6ULG" FT HELIX 283..290 FT /evidence="ECO:0007829|PDB:6ULG" FT STRAND 340..343 FT /evidence="ECO:0007829|PDB:6ULG" FT HELIX 349..356 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 358..370 FT /evidence="ECO:0007829|PDB:3V42" FT STRAND 373..377 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 381..391 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 392..394 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 397..399 FT /evidence="ECO:0007829|PDB:3V42" FT STRAND 402..408 FT /evidence="ECO:0007829|PDB:3V42" FT TURN 412..414 FT /evidence="ECO:0007829|PDB:3V42" FT STRAND 416..420 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 424..427 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 428..431 FT /evidence="ECO:0007829|PDB:3V42" FT STRAND 436..443 FT /evidence="ECO:0007829|PDB:3V42" FT STRAND 463..469 FT /evidence="ECO:0007829|PDB:3V42" FT TURN 473..476 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 481..491 FT /evidence="ECO:0007829|PDB:3V42" FT STRAND 493..495 FT /evidence="ECO:0007829|PDB:6ULG" FT HELIX 497..521 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 530..538 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 544..553 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 554..556 FT /evidence="ECO:0007829|PDB:3V42" FT HELIX 559..567 FT /evidence="ECO:0007829|PDB:6ULG" SQ SEQUENCE 579 AA; 64473 MW; E168EB34544C6336 CRC64; MNAIVALCHF CELHGPRTLF CTEVLHAPLP QGDGNEDSPG QGEQAEEEEG GIQMNSRMRA HSPAEGASVE SSSPGPKKSD MCEGCRSLAA GHPGYISHDK ETSIKYVSHQ HPSHPQLFSI VRQACVRSLS CEVCPGREGP IFFGDEQHGF VFSHTFFIKD SLARGFQRWY SIITIMMDRI YLINSWPFLL GKVRGIIDEL QGKALKVFEA EQFGCPQRAQ RMNTAFTPFL HQRNGNAARS LTSLTSDDNL WACLHTSFAW LLKACGSRLT EKLLEGAPTE DTLVQMEKLA DLEEESESWD NSEAEEEEKA PVLPESTEGR ELTQGPAESS SLSGCGSWQP RKLPVFKSLR HMRQVLGAPS FRMLAWHVLM GNQVIWKSRD VDLVQSAFEV LRTMLPVGCV RIIPYSSQYE EAYRCNFLGL SPHVQIPPHV LSSEFAVIVE VHAAARSTLH PVGCEDDQSL SKYEFVVTSG SPVAADRVGP TILNKIEAAL TNQNLSVDVV DQCLVCLKEE WMNKVKVLFK FTKVDSRPKE DTQKLLSILG ASEEDNVKLL KFWMTGLSKT YKSHLMSTVR SPTASESRN //