ID TSC1_HUMAN Reviewed; 1164 AA. AC Q92574; B7Z897; Q5VVN5; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 2. DT 27-MAR-2024, entry version 217. DE RecName: Full=Hamartin {ECO:0000303|PubMed:9809973}; DE AltName: Full=Tuberous sclerosis 1 protein {ECO:0000303|PubMed:9242607}; GN Name=TSC1 {ECO:0000303|PubMed:9242607, ECO:0000312|HGNC:HGNC:12362}; GN Synonyms=KIAA0243 {ECO:0000303|PubMed:9039502}, TSC; 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), FUNCTION, TISSUE SPECIFICITY, AND RP VARIANT ARG-587. RX PubMed=9242607; DOI=10.1126/science.277.5327.805; RA van Slegtenhorst M.A., de Hoogt R., Hermans C., Nellist M., Janssen B., RA Verhoef S., Lindhout D., van den Ouweland A.M.W., Halley D.J.J., Young J., RA Burley M., Jeremiah S., Woodward K., Nahmias J., Fox M., Ekong R., RA Osborne J., Wolfe J., Povey S., Snell R.G., Cheadle J.P., Jones A.C., RA Tachataki M., Ravine D., Sampson J.R., Reeve M.P., Richardson P., RA Wilmer F., Munro C., Hawkins T.L., Sepp T., Ali J.B.M., Ward S., RA Green A.J., Yates J.R.W., Kwiatkowska J., Henske E.P., Short M.P., RA Haines J.H., Jozwiak S., Kwiatkowski D.J.; RT "Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34."; RL Science 277:805-808(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Testis; 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=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., RA Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 466-1164 (ISOFORM 1/2). RC TISSUE=Bone marrow; RX PubMed=9039502; DOI=10.1093/dnares/3.5.321; RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O., RA Tanaka A., Kotani H., Miyajima N., Nomura N.; RT "Prediction of the coding sequences of unidentified human genes. VI. The RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of RT cDNA clones from cell line KG-1 and brain."; RL DNA Res. 3:321-329(1996). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 568-586. RA Fang L., Wang N., Murong S.X., Wu Z.Y., Lin M.T.; RT "A silent mutation 1947 T-->C in exon 15 of TSC1 in Chinese."; RL Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases. RN [7] RP SUBCELLULAR LOCATION, AND INTERACTION WITH TSC2. RX PubMed=9809973; RA Plank T.L., Yeung R.S., Henske E.P.; RT "Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts RT with tuberin and appears to be localized to cytoplasmic vesicles."; RL Cancer Res. 58:4766-4770(1998). RN [8] RP INTERACTION WITH TSC2. RX PubMed=9580671; DOI=10.1093/hmg/7.6.1053; RA van Slegtenhorst M.A., Nellist M., Nagelkerken B., Cheadle J.P., RA Snell R.G., van den Ouweland A.M.W., Reuser A., Sampson J.R., RA Halley D.J.J., van der Sluijs P.; RT "Interaction between hamartin and tuberin, the TSC1 and TSC2 gene RT products."; RL Hum. Mol. Genet. 7:1053-1057(1998). RN [9] RP INTERACTION WITH TSC2. RX PubMed=10585443; DOI=10.1074/jbc.274.50.35647; RA Nellist M., van Slegtenhorst M.A., Goedbloed M., van den Ouweland A.M.W., RA Halley D.J.J., van der Sluijs P.; RT "Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a RT cytosolic chaperone for hamartin."; RL J. Biol. Chem. 274:35647-35652(1999). RN [10] RP FUNCTION, AND INTERACTION WITH TSC2. RX PubMed=12172553; DOI=10.1038/ncb839; RA Inoki K., Li Y., Zhu T., Wu J., Guan K.L.; RT "TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR RT signalling."; RL Nat. Cell Biol. 4:648-657(2002). RN [11] RP FUNCTION, AND INTERACTION WITH TSC2. RX PubMed=12906785; DOI=10.1016/s0960-9822(03)00506-2; RA Tee A.R., Manning B.D., Roux P.P., Cantley L.C., Blenis J.; RT "Tuberous sclerosis complex gene products, Tuberin and Hamartin, control RT mTOR signaling by acting as a GTPase-activating protein complex toward RT Rheb."; RL Curr. Biol. 13:1259-1268(2003). RN [12] RP INVOLVEMENT IN LAM, AND VARIANT TSC1 165-CYS--SER-1164 DEL. RX PubMed=11829138; DOI=10.1007/s10038-002-8651-8; RA Sato T., Seyama K., Fujii H., Maruyama H., Setoguchi Y., Iwakami S., RA Fukuchi Y., Hino O.; RT "Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with RT pulmonary lymphangioleiomyomatosis."; RL J. Hum. Genet. 47:20-28(2002). RN [13] RP FUNCTION. RX PubMed=12271141; DOI=10.1073/pnas.202476899; RA Tee A.R., Fingar D.C., Manning B.D., Kwiatkowski D.J., Cantley L.C., RA Blenis J.; RT "Tuberous sclerosis complex-1 and -2 gene products function together to RT inhibit mammalian target of rapamycin (mTOR)-mediated downstream RT signaling."; RL Proc. Natl. Acad. Sci. U.S.A. 99:13571-13576(2002). RN [14] RP FUNCTION. RX PubMed=15340059; DOI=10.1128/mcb.24.18.7965-7975.2004; RA Li Y., Inoki K., Guan K.-L.; RT "Biochemical and functional characterizations of small GTPase Rheb and TSC2 RT GAP activity."; RL Mol. Cell. Biol. 24:7965-7975(2004). RN [15] RP PHOSPHORYLATION AT SER-505, IDENTIFICATION BY MASS SPECTROMETRY, AND RP INTERACTION WITH DOCK7 AND TSC2. RX PubMed=15963462; DOI=10.1016/j.bbrc.2005.05.175; RA Nellist M., Burgers P.C., van den Ouweland A.M.W., Halley D.J.J., RA Luider T.M.; RT "Phosphorylation and binding partner analysis of the TSC1-TSC2 complex."; RL Biochem. Biophys. Res. Commun. 333:818-826(2005). RN [16] RP FUNCTION, AND INTERACTION WITH TSC2. RX PubMed=16464865; DOI=10.1074/jbc.c500451200; RA Chong-Kopera H., Inoki K., Li Y., Zhu T., Garcia-Gonzalo F.R., Rosa J.L., RA Guan K.-L.; RT "TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the RT HERC1 ubiquitin ligase."; RL J. Biol. Chem. 281:8313-8316(2006). RN [17] RP INTERACTION WITH TBC1D7. RX PubMed=17658474; DOI=10.1016/j.bbrc.2007.07.011; RA Nakashima A., Yoshino K., Miyamoto T., Eguchi S., Oshiro N., Kikkawa U., RA Yonezawa K.; RT "Identification of TBC7 having TBC domain as a novel binding protein to RT TSC1-TSC2 complex."; RL Biochem. Biophys. Res. Commun. 361:218-223(2007). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic kidney; RX PubMed=17525332; DOI=10.1126/science.1140321; RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., RA Gygi S.P., Elledge S.J.; RT "ATM and ATR substrate analysis reveals extensive protein networks RT responsive to DNA damage."; RL Science 316:1160-1166(2007). RN [19] RP INTERACTION WITH FBXW5. RX PubMed=18381890; DOI=10.1101/gad.1624008; RA Hu J., Zacharek S., He Y.J., Lee H., Shumway S., Duronio R.J., Xiong Y.; RT "WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by RT DDB1-CUL4-ROC1 ligase."; RL Genes Dev. 22:866-871(2008). RN [20] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Platelet; RX PubMed=18088087; DOI=10.1021/pr0704130; RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., RA Schuetz C., Walter U., Gambaryan S., Sickmann A.; RT "Phosphoproteome of resting human platelets."; RL J. Proteome Res. 7:526-534(2008). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-505; SER-511 AND SER-598, AND RP IDENTIFICATION BY 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 [22] 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 [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-505, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [24] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [25] RP IDENTIFICATION IN THE TSC-TBC COMPLEX. RX PubMed=22795129; DOI=10.1016/j.molcel.2012.06.009; RA Dibble C.C., Elis W., Menon S., Qin W., Klekota J., Asara J.M., Finan P.M., RA Kwiatkowski D.J., Murphy L.O., Manning B.D.; RT "TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1."; RL Mol. Cell 47:535-546(2012). RN [26] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-487; SER-505 AND SER-521, AND RP 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 [27] RP FUNCTION, IDENTIFICATION IN THE TSC-TBC COMPLEX, AND SUBCELLULAR LOCATION. RX PubMed=24529379; DOI=10.1016/j.cell.2013.11.049; RA Menon S., Dibble C.C., Talbott G., Hoxhaj G., Valvezan A.J., Takahashi H., RA Cantley L.C., Manning B.D.; RT "Spatial control of the TSC complex integrates insulin and nutrient RT regulation of mTORC1 at the lysosome."; RL Cell 156:771-785(2014). RN [28] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1100, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [29] RP FUNCTION, INTERACTION WITH TSC2, INVOLVEMENT IN FCORD2, VARIANTS FCORD2 RP TRP-22 AND CYS-204, AND CHARACTERIZATION OF VARIANTS FCORD2 TRP-22 AND RP CYS-204. RX PubMed=28215400; DOI=10.1016/j.ajhg.2017.01.030; RA Lim J.S., Gopalappa R., Kim S.H., Ramakrishna S., Lee M., Kim W.I., Kim J., RA Park S.M., Lee J., Oh J.H., Kim H.D., Park C.H., Lee J.S., Kim S., RA Kim D.S., Han J.M., Kang H.C., Kim H.H., Lee J.H.; RT "Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia."; RL Am. J. Hum. Genet. 100:454-472(2017). RN [30] RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH HSP90; HSP70; STIP1; CDC37; RP PPP5C; PTGES3; TSC2; AKT; CDK4; RAF1 AND NR3C1, INTERACTION WITH HSP90AA1 RP AND TSC2, AND VARIANT PRO-117. RX PubMed=29127155; DOI=10.15252/embj.201796700; RA Woodford M.R., Sager R.A., Marris E., Dunn D.M., Blanden A.R., Murphy R.L., RA Rensing N., Shapiro O., Panaretou B., Prodromou C., Loh S.N., Gutmann D.H., RA Bourboulia D., Bratslavsky G., Wong M., Mollapour M.; RT "Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding RT of kinase and non-kinase clients."; RL EMBO J. 36:3650-3665(2017). RN [31] RP INTERACTION WITH RPAP3 AND URI1. RX PubMed=28561026; DOI=10.1038/ncomms15615; RA Cloutier P., Poitras C., Durand M., Hekmat O., Fiola-Masson E., RA Bouchard A., Faubert D., Chabot B., Coulombe B.; RT "R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 RT to regulate assembly of U5 small nuclear ribonucleoprotein."; RL Nat. Commun. 8:15615-15615(2017). RN [32] RP INTERACTION WITH WDR45B, AND REGION. RX PubMed=28561066; DOI=10.1038/ncomms15637; RA Bakula D., Mueller A.J., Zuleger T., Takacs Z., Franz-Wachtel M., RA Thost A.K., Brigger D., Tschan M.P., Frickey T., Robenek H., Macek B., RA Proikas-Cezanne T.; RT "WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling RT circuits in the control of autophagy."; RL Nat. Commun. 8:15637-15637(2017). RN [33] {ECO:0007744|PDB:5EJC} RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 939-992 IN COMPLEX WITH TBC1D7, RP INTERACTION WITH TBC1D7, AND MUTAGENESIS OF LEU-941; 954-ILE--ILE-962; RP ILE-954; PHE-958; ILE-962 AND 965-LEU--LEU-969. RX PubMed=26893383; DOI=10.1074/jbc.m115.701870; RA Qin J., Wang Z., Hoogeveen-Westerveld M., Shen G., Gong W., Nellist M., RA Xu W.; RT "Structural basis of the interaction between tuberous sclerosis complex 1 RT (TSC1) and Tre2-Bub2-Cdc16 domain family member 7 (TBC1D7)."; RL J. Biol. Chem. 291:8591-8601(2016). RN [34] {ECO:0007744|PDB:7DL2} RP STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS) IN COMPLEX WITH TBC1D7 RP AND TSC2, AND IDENTIFICATION IN THE TSC-TBC COMPLEX. RX PubMed=33436626; DOI=10.1038/s41467-020-20522-4; RA Yang H., Yu Z., Chen X., Li J., Li N., Cheng J., Gao N., Yuan H.X., Ye D., RA Guan K.L., Xu Y.; RT "Structural insights into TSC complex assembly and GAP activity on Rheb."; RL Nat. Commun. 12:339-339(2021). RN [35] RP VARIANT TSC1 GLU-726, AND VARIANTS THR-322; TYR-732 AND SER-1035. RC TISSUE=Peripheral blood; RX PubMed=9328481; DOI=10.1093/hmg/6.12.2155; RA Jones A.C., Daniells C.E., Snell R.G., Tachataki M., Idziaszczyk S.A., RA Krawczak M., Sampson J.R., Cheadle J.P.; RT "Molecular genetic and phenotypic analysis reveals differences between TSC1 RT and TSC2 associated familial and sporadic tuberous sclerosis."; RL Hum. Mol. Genet. 6:2155-2161(1997). RN [36] RP VARIANTS THR-322; ARG-587; TYR-732; SER-1035 AND SER-1108. RC TISSUE=Blood; RX PubMed=9924605; DOI=10.1046/j.1469-1809.1998.6240277.x; RA Kwiatkowska J., Jozwiak S., Hall F., Henske E.P., Haines J.L., McNamara P., RA Braiser J., Wigowska-Sowinska J., Kasprzyk-Obara J., Short M.P., RA Kwiatkowski D.J.; RT "Comprehensive mutational analysis of the TSC1 gene: observations on RT frequency of mutation, associated features, and nonpenetrance."; RL Ann. Hum. Genet. 62:277-285(1998). RN [37] RP VARIANT TSC1 PRO-72. RX PubMed=10533069; RX DOI=10.1002/(sici)1098-1004(199911)14:5<428::aid-humu9>3.0.co;2-5; RA Benit P., Kara-Mostefa A., Hadj-Rabia S., Munnich A., Bonnefont J.-P.; RT "Protein truncation test for screening hamartin gene mutations and report RT of new disease-causing mutations."; RL Hum. Mutat. 14:428-432(1999). RN [38] RP VARIANTS THR-322; TYR-732 AND GLN-809. RC TISSUE=Blood, and Lymphoblast; RX PubMed=10533067; RX DOI=10.1002/(sici)1098-1004(199911)14:5<412::aid-humu7>3.0.co;2-k; RA Niida Y., Lawrence-Smith N., Banwell A., Hammer E., Lewis J., RA Beauchamp R.L., Sims K., Ramesh V., Ozelius L.; RT "Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated RT patients with tuberous sclerosis."; RL Hum. Mutat. 14:412-422(1999). RN [39] RP VARIANTS TSC1 ILE-417; GLU-654 AND SER-899, AND VARIANT THR-322. RC TISSUE=Blood; RX PubMed=10570911; DOI=10.1007/s100380050185; RA Zhang H., Nanba E., Yamamoto T., Ninomiya H., Ohno K., Mizuguchi M., RA Takeshita K.; RT "Mutational analysis of TSC1 and TSC2 genes in Japanese patients with RT tuberous sclerosis complex."; RL J. Hum. Genet. 44:391-396(1999). RN [40] RP VARIANTS TSC1, AND VARIANTS. RC TISSUE=Peripheral blood; RX PubMed=10227394; RA Van Slegtenhorst M.A., Verhoef S., Tempelaars A., Bakker L., Wang Q., RA Wessels M., Bakker R., Nellist M., Lindhout D., Halley D.J.J., RA van den Ouweland A.M.W.; RT "Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis RT complex patients: no evidence for genotype-phenotype correlation."; RL J. Med. Genet. 36:285-289(1999). RN [41] RP VARIANTS THR-322; ILE-417; ASP-577 AND ARG-829. RC TISSUE=Peripheral blood leukocyte; RX PubMed=10607950; RX DOI=10.1002/(sici)1096-8628(20000117)90:2<123::aid-ajmg7>3.3.co;2-c; RA Yamashita Y., Ono J., Okada S., Wataya-Kaneda M., Yoshikawa K., RA Nishizawa M., Hirayama Y., Kobayashi E., Seyama K., Hino O.; RT "Analysis of all exons of TSC1 and TSC2 genes for germline mutations in RT Japanese patients with tuberous sclerosis: report of 10 mutations."; RL Am. J. Med. Genet. 90:123-126(2000). RN [42] RP VARIANT TSC1 GLN-500. RX PubMed=10874311; RX DOI=10.1002/1098-1004(200007)16:1<88::aid-humu15>3.0.co;2-j; RA Hass J., Mayer K., Rott H.-D.; RT "Tuberous sclerosis type 1: three novel mutations detected in exon 15 by a RT combination of HDA and TGGE."; RL Hum. Mutat. 16:88-88(2000). RN [43] RP VARIANT TYR-732. RX PubMed=12112044; DOI=10.1002/ana.10251; RA Becker A.J., Urbach H., Scheffler B., Baden T., Normann S., Lahl R., RA Pannek H.W., Tuxhorn I., Elger C.E., Schramm J., Wiestler O.D., RA Bluemcke I.; RT "Focal cortical dysplasia of Taylor's balloon cell type: mutational RT analysis of the TSC1 gene indicates a pathogenic relationship to tuberous RT sclerosis."; RL Ann. Neurol. 52:29-37(2002). RN [44] RP VARIANTS ARG-68; CYS-158; ASP-206; LEU-216 AND ILE-417, AND RP CHARACTERIZATION OF VARIANTS ARG-68; CYS-158; ASP-206; LEU-216 AND ILE-417. RX PubMed=18397877; DOI=10.1093/hmg/ddn098; RA Pymar L.S., Platt F.M., Askham J.M., Morrison E.E., Knowles M.A.; RT "Bladder tumour-derived somatic TSC1 missense mutations cause loss of RT function via distinct mechanisms."; RL Hum. Mol. Genet. 17:2006-2017(2008). RN [45] RP VARIANTS TSC1 PRO-117; VAL-128 DEL; PRO-180; HIS-191; 198-ASN-PHE-199 RP DELINS ILE; ARG-224; LYS-246; ARG-305 AND TRP-305, VARIANTS GLN-509; RP SER-1035 AND HIS-1097, CHARACTERIZATION OF VARIANTS TSC1 PRO-117; VAL-128 RP DEL; PRO-180; HIS-191; 198-ASN-PHE-199 DELINS ILE; ARG-224; LYS-246; RP ARG-305 AND TRP-305, AND CHARACTERIZATION OF VARIANTS GLN-509; SER-1035 AND RP HIS-1097. RX PubMed=18830229; DOI=10.1038/ejhg.2008.170; RA Nellist M., van den Heuvel D., Schluep D., Exalto C., Goedbloed M., RA Maat-Kievit A., van Essen T., van Spaendonck-Zwarts K., Jansen F., RA Helderman P., Bartalini G., Vierimaa O., Penttinen M., van den Ende J., RA van den Ouweland A., Halley D.; RT "Missense mutations to the TSC1 gene cause tuberous sclerosis complex."; RL Eur. J. Hum. Genet. 17:319-328(2009). RN [46] RP VARIANTS TSC1 ARG-61; ILE-126; ASP-132; ILE-133; GLN-336; SER-362; ILE-411; RP PRO-523; HIS-693; ARG-698; HIS-701; SER-762; GLY-811; THR-883; VAL-978; RP SER-1043 DEL AND TYR-1146, VARIANTS SER-158; PRO-204; SER-448 AND VAL-567, RP CHARACTERIZATION OF VARIANTS TSC1 ARG-61; PRO-117; ILE-126; ASP-132; RP ILE-133; GLN-336; SER-362; ILE-411; PRO-523; HIS-693; ARG-698; HIS-701; RP SER-762; GLY-811; THR-883; VAL-978; SER-1043 DEL AND TYR-1146, AND RP CHARACTERIZATION OF VARIANTS SER-158; PRO-204; SER-448 AND VAL-567. RX PubMed=22161988; DOI=10.1002/humu.22007; RA Hoogeveen-Westerveld M., Ekong R., Povey S., Karbassi I., Batish S.D., RA den Dunnen J.T., van Eeghen A., Thiele E., Mayer K., Dies K., Wen L., RA Thompson C., Sparagana S.P., Davies P., Aalfs C., van den Ouweland A., RA Halley D., Nellist M.; RT "Functional assessment of TSC1 missense variants identified in individuals RT with tuberous sclerosis complex."; RL Hum. Mutat. 33:476-479(2012). CC -!- FUNCTION: Non-catalytic component of the TSC-TBC complex, a CC multiprotein complex that acts as a negative regulator of the canonical CC mTORC1 complex, an evolutionarily conserved central nutrient sensor CC that stimulates anabolic reactions and macromolecule biosynthesis to CC promote cellular biomass generation and growth (PubMed:12172553, CC PubMed:12906785, PubMed:12271141, PubMed:28215400, PubMed:15340059, CC PubMed:24529379). The TSC-TBC complex acts as a GTPase-activating CC protein (GAP) for the small GTPase RHEB, a direct activator of the CC protein kinase activity of mTORC1 (PubMed:12906785, PubMed:15340059, CC PubMed:24529379). In absence of nutrients, the TSC-TBC complex inhibits CC mTORC1, thereby preventing phosphorylation of ribosomal protein S6 CC kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 CC signaling (PubMed:12271141, PubMed:24529379, PubMed:28215400). The TSC- CC TBC complex is inactivated in response to nutrients, relieving CC inhibition of mTORC1 (PubMed:12172553, PubMed:24529379). Within the CC TSC-TBC complex, TSC1 stabilizes TSC2 and prevents TSC2 self- CC aggregation (PubMed:10585443, PubMed:28215400). Acts as a tumor CC suppressor (PubMed:9242607). Involved in microtubule-mediated protein CC transport via its ability to regulate mTORC1 signaling (By similarity). CC Also acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 CC chaperoning of protein clients such as kinases, TSC2 and glucocorticoid CC receptor NR3C1 (PubMed:29127155). Increases ATP binding to HSP90AA1 and CC inhibits HSP90AA1 ATPase activity (PubMed:29127155). Competes with the CC activating co-chaperone AHSA1 for binding to HSP90AA1, thereby CC providing a reciprocal regulatory mechanism for chaperoning of client CC proteins (PubMed:29127155). Recruits TSC2 to HSP90AA1 and stabilizes CC TSC2 by preventing the interaction between TSC2 and ubiquitin ligase CC HERC1 (PubMed:16464865, PubMed:29127155). CC {ECO:0000250|UniProtKB:Q9Z136, ECO:0000269|PubMed:10585443, CC ECO:0000269|PubMed:12172553, ECO:0000269|PubMed:12271141, CC ECO:0000269|PubMed:12906785, ECO:0000269|PubMed:15340059, CC ECO:0000269|PubMed:16464865, ECO:0000269|PubMed:24529379, CC ECO:0000269|PubMed:28215400, ECO:0000269|PubMed:29127155, CC ECO:0000269|PubMed:9242607}. CC -!- SUBUNIT: Component of the TSC-TBC complex (also named Rhebulator CC complex), composed of 2 molecules of TSC1, 2 molecules of TSC2 and 1 CC molecule of TBC1D7 (PubMed:9809973, PubMed:9580671, PubMed:10585443, CC PubMed:12172553, PubMed:12906785, PubMed:16464865, PubMed:17658474, CC PubMed:28215400, PubMed:15963462, PubMed:22795129, PubMed:24529379, CC PubMed:26893383, PubMed:33436626). Probably forms a complex composed of CC chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, CC PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Forms a CC complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, CC PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this CC complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 CC (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2; CC TSC1 is required to recruit TCS2 to the complex (PubMed:29127155). CC Interacts (via C-terminus) with the closed form of HSP90AA1 (via the CC middle domain and TPR repeat-binding motif) (PubMed:29127155). CC Interacts with DOCK7 (PubMed:15963462). Interacts with FBXW5 CC (PubMed:18381890). Interacts with WDR45B (PubMed:28561066). Interacts CC with RPAP3 and URI1 (PubMed:28561026). {ECO:0000269|PubMed:10585443, CC ECO:0000269|PubMed:12172553, ECO:0000269|PubMed:12906785, CC ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:16464865, CC ECO:0000269|PubMed:17658474, ECO:0000269|PubMed:18381890, CC ECO:0000269|PubMed:22795129, ECO:0000269|PubMed:24529379, CC ECO:0000269|PubMed:26893383, ECO:0000269|PubMed:28215400, CC ECO:0000269|PubMed:28561026, ECO:0000269|PubMed:28561066, CC ECO:0000269|PubMed:29127155, ECO:0000269|PubMed:33436626, CC ECO:0000269|PubMed:9580671, ECO:0000269|PubMed:9809973}. CC -!- INTERACTION: CC Q92574; Q00994: BEX3; NbExp=5; IntAct=EBI-1047085, EBI-741753; CC Q92574; P02794: FTH1; NbExp=3; IntAct=EBI-1047085, EBI-713259; CC Q92574; O14920: IKBKB; NbExp=3; IntAct=EBI-1047085, EBI-81266; CC Q92574; Q674X7: KAZN; NbExp=2; IntAct=EBI-1047085, EBI-949239; CC Q92574; Q16539: MAPK14; NbExp=2; IntAct=EBI-1047085, EBI-73946; CC Q92574; Q9NRD5: PICK1; NbExp=2; IntAct=EBI-1047085, EBI-79165; CC Q92574; Q92844: TANK; NbExp=3; IntAct=EBI-1047085, EBI-356349; CC Q92574; Q9P0N9: TBC1D7; NbExp=3; IntAct=EBI-1047085, EBI-3258000; CC Q92574; P49815: TSC2; NbExp=13; IntAct=EBI-1047085, EBI-396587; CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:24529379}; CC Peripheral membrane protein {ECO:0000269|PubMed:9809973}. Cytoplasm, CC cytosol {ECO:0000269|PubMed:24529379, ECO:0000269|PubMed:9809973}. CC Note=Recruited to lysosomal membranes in a RHEB-dependent process in CC absence of nutrients (PubMed:24529379). In response to nutrients, the CC complex dissociates from lysosomal membranes and relocalizes to the CC cytosol (PubMed:24529379). {ECO:0000269|PubMed:24529379}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q92574-1; Sequence=Displayed; CC Name=2; CC IsoId=Q92574-2; Sequence=VSP_042890; CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle, followed by CC heart, brain, placenta, pancreas, lung, liver and kidney CC (PubMed:9242607). Also expressed in embryonic kidney cells CC (PubMed:9242607). {ECO:0000269|PubMed:9242607}. CC -!- DOMAIN: The C-terminal putative coiled-coil domain is necessary for CC interaction with TSC2. {ECO:0000269|PubMed:9580671}. CC -!- PTM: Phosphorylation at Ser-505 does not affect interaction with TSC2. CC {ECO:0000269|PubMed:15963462}. CC -!- DISEASE: Tuberous sclerosis 1 (TSC1) [MIM:191100]: An autosomal CC dominant multi-system disorder that affects especially the brain, CC kidneys, heart, and skin. It is characterized by hamartomas (benign CC overgrowths predominantly of a cell or tissue type that occurs normally CC in the organ) and hamartias (developmental abnormalities of tissue CC combination). Clinical manifestations include epilepsy, learning CC difficulties, behavioral problems, and skin lesions. Seizures can be CC intractable and premature death can occur from a variety of disease- CC associated causes. {ECO:0000269|PubMed:10227394, CC ECO:0000269|PubMed:10533069, ECO:0000269|PubMed:10570911, CC ECO:0000269|PubMed:10874311, ECO:0000269|PubMed:11829138, CC ECO:0000269|PubMed:18830229, ECO:0000269|PubMed:22161988, CC ECO:0000269|PubMed:9328481}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Lymphangioleiomyomatosis (LAM) [MIM:606690]: Progressive and CC often fatal lung disease characterized by a diffuse proliferation of CC abnormal smooth muscle cells in the lungs. It affects almost CC exclusively young women and can occur as an isolated disorder or in CC association with tuberous sclerosis complex. CC {ECO:0000269|PubMed:11829138}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Focal cortical dysplasia 2 (FCORD2) [MIM:607341]: A form of CC focal cortical dysplasia, a malformation of cortical development that CC results in medically refractory epilepsy in the pediatric population CC and in adults. FCORD2 is a severe form, with onset usually in CC childhood, characterized by disrupted cortical lamination and specific CC cytological abnormalities. It is classified in 2 subtypes: type IIA CC characterized by dysmorphic neurons and lack of balloon cells; type IIB CC with dysmorphic neurons and balloon cells. CC {ECO:0000269|PubMed:28215400}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/183/TSC1"; CC -!- WEB RESOURCE: Name=Tuberous sclerosis database Tuberous sclerosis 1 CC (TSC1); Note=Leiden Open Variation Database (LOVD); CC URL="https://databases.lovd.nl/shared/genes/TSC1"; 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; AF013168; AAC51674.1; -; mRNA. DR EMBL; AK303030; BAH13883.1; -; mRNA. DR EMBL; AL445645; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471090; EAW88021.1; -; Genomic_DNA. DR EMBL; AC002096; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; D87683; BAA13436.1; -; mRNA. DR EMBL; AF234185; AAF61948.1; -; Genomic_DNA. DR CCDS; CCDS55350.1; -. [Q92574-2] DR CCDS; CCDS6956.1; -. [Q92574-1] DR PIR; T03814; T03814. DR RefSeq; NP_000359.1; NM_000368.4. [Q92574-1] DR RefSeq; NP_001155898.1; NM_001162426.1. DR RefSeq; NP_001155899.1; NM_001162427.1. [Q92574-2] DR RefSeq; XP_005272268.1; XM_005272211.1. DR RefSeq; XP_006717334.1; XM_006717271.1. DR RefSeq; XP_011517281.1; XM_011518979.2. [Q92574-1] DR RefSeq; XP_016870585.1; XM_017015096.1. DR RefSeq; XP_016870586.1; XM_017015097.1. DR PDB; 4Z6Y; X-ray; 2.81 A; C/D/F/H=938-993. DR PDB; 5EJC; X-ray; 3.10 A; C/D/E/F=939-992. DR PDB; 7DL2; EM; 4.40 A; C/D=1-1164. DR PDBsum; 4Z6Y; -. DR PDBsum; 5EJC; -. DR PDBsum; 7DL2; -. DR AlphaFoldDB; Q92574; -. DR EMDB; EMD-11816; -. DR EMDB; EMD-11817; -. DR EMDB; EMD-11819; -. DR EMDB; EMD-30708; -. DR SMR; Q92574; -. DR BioGRID; 113099; 281. DR ComplexPortal; CPX-6142; TSC1-TSC2 complex. DR CORUM; Q92574; -. DR IntAct; Q92574; 125. DR MINT; Q92574; -. DR STRING; 9606.ENSP00000298552; -. DR CarbonylDB; Q92574; -. DR GlyGen; Q92574; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q92574; -. DR PhosphoSitePlus; Q92574; -. DR BioMuta; TSC1; -. DR DMDM; 9297077; -. DR EPD; Q92574; -. DR jPOST; Q92574; -. DR MassIVE; Q92574; -. DR MaxQB; Q92574; -. DR PaxDb; 9606-ENSP00000298552; -. DR PeptideAtlas; Q92574; -. DR ProteomicsDB; 75334; -. [Q92574-1] DR ProteomicsDB; 75335; -. [Q92574-2] DR Pumba; Q92574; -. DR Antibodypedia; 3164; 1995 antibodies from 46 providers. DR DNASU; 7248; -. DR Ensembl; ENST00000298552.9; ENSP00000298552.3; ENSG00000165699.15. [Q92574-1] DR Ensembl; ENST00000440111.6; ENSP00000394524.2; ENSG00000165699.15. [Q92574-1] DR Ensembl; ENST00000490179.4; ENSP00000495533.2; ENSG00000165699.15. [Q92574-1] DR Ensembl; ENST00000545250.5; ENSP00000444017.1; ENSG00000165699.15. [Q92574-2] DR Ensembl; ENST00000643072.1; ENSP00000496691.1; ENSG00000165699.15. [Q92574-2] DR Ensembl; ENST00000643875.1; ENSP00000495158.1; ENSG00000165699.15. [Q92574-1] DR Ensembl; ENST00000646440.2; ENSP00000495830.2; ENSG00000165699.15. [Q92574-1] DR Ensembl; ENST00000646625.1; ENSP00000496263.1; ENSG00000165699.15. [Q92574-1] DR GeneID; 7248; -. DR KEGG; hsa:7248; -. DR MANE-Select; ENST00000298552.9; ENSP00000298552.3; NM_000368.5; NP_000359.1. DR UCSC; uc064wss.1; human. [Q92574-1] DR AGR; HGNC:12362; -. DR CTD; 7248; -. DR DisGeNET; 7248; -. DR GeneCards; TSC1; -. DR GeneReviews; TSC1; -. DR HGNC; HGNC:12362; TSC1. DR HPA; ENSG00000165699; Low tissue specificity. DR MalaCards; TSC1; -. DR MIM; 191100; phenotype. DR MIM; 605284; gene. DR MIM; 606690; phenotype. DR MIM; 607341; phenotype. DR neXtProt; NX_Q92574; -. DR OpenTargets; ENSG00000165699; -. DR Orphanet; 210159; Adult hepatocellular carcinoma. DR Orphanet; 269008; Isolated focal cortical dysplasia type IIb. DR Orphanet; 538; Lymphangioleiomyomatosis. DR Orphanet; 805; Tuberous sclerosis complex. DR PharmGKB; PA37034; -. DR VEuPathDB; HostDB:ENSG00000165699; -. DR eggNOG; ENOG502QQPT; Eukaryota. DR GeneTree; ENSGT00390000014148; -. DR HOGENOM; CLU_011546_0_0_1; -. DR InParanoid; Q92574; -. DR OMA; NRMASYS; -. DR OrthoDB; 4251017at2759; -. DR PhylomeDB; Q92574; -. DR TreeFam; TF325466; -. DR PathwayCommons; Q92574; -. DR Reactome; R-HSA-1632852; Macroautophagy. DR Reactome; R-HSA-165181; Inhibition of TSC complex formation by PKB. DR Reactome; R-HSA-380972; Energy dependent regulation of mTOR by LKB1-AMPK. DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes. DR Reactome; R-HSA-8854214; TBC/RABGAPs. DR SABIO-RK; Q92574; -. DR SignaLink; Q92574; -. DR SIGNOR; Q92574; -. DR BioGRID-ORCS; 7248; 93 hits in 1187 CRISPR screens. DR ChiTaRS; TSC1; human. DR GeneWiki; TSC1; -. DR GenomeRNAi; 7248; -. DR Pharos; Q92574; Tbio. DR PRO; PR:Q92574; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; Q92574; Protein. DR Bgee; ENSG00000165699; Expressed in substantia nigra pars compacta and 214 other cell types or tissues. DR ExpressionAtlas; Q92574; baseline and differential. DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0030027; C:lamellipodium; IDA:UniProtKB. DR GO; GO:0005811; C:lipid droplet; IDA:HPA. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; ISS:ParkinsonsUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:ParkinsonsUK-UCL. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl. DR GO; GO:0101031; C:protein folding chaperone complex; IDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0033596; C:TSC1-TSC2 complex; IDA:UniProtKB. DR GO; GO:0042030; F:ATPase inhibitor activity; IDA:UniProtKB. DR GO; GO:0030544; F:Hsp70 protein binding; IDA:UniProtKB. DR GO; GO:0051879; F:Hsp90 protein binding; IPI:UniProtKB. DR GO; GO:0051087; F:protein-folding chaperone binding; IPI:UniProtKB. DR GO; GO:0090630; P:activation of GTPase activity; IDA:UniProtKB. DR GO; GO:0002250; P:adaptive immune response; IEA:Ensembl. DR GO; GO:0008344; P:adult locomotory behavior; ISS:ParkinsonsUK-UCL. DR GO; GO:0008306; P:associative learning; IEA:Ensembl. DR GO; GO:0055007; P:cardiac muscle cell differentiation; IEA:Ensembl. DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl. DR GO; GO:0030030; P:cell projection organization; IEA:Ensembl. DR GO; GO:0007160; P:cell-matrix adhesion; IMP:UniProtKB. DR GO; GO:0036294; P:cellular response to decreased oxygen levels; ISS:ParkinsonsUK-UCL. DR GO; GO:0009267; P:cellular response to starvation; IDA:UniProtKB. DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl. DR GO; GO:0046323; P:glucose import; IEA:Ensembl. DR GO; GO:0021766; P:hippocampus development; IEA:Ensembl. DR GO; GO:0001822; P:kidney development; IEA:Ensembl. DR GO; GO:0043379; P:memory T cell differentiation; IEA:Ensembl. DR GO; GO:0042552; P:myelination; IEA:Ensembl. DR GO; GO:0032780; P:negative regulation of ATP-dependent activity; IDA:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:UniProtKB. DR GO; GO:0045792; P:negative regulation of cell size; IEA:Ensembl. DR GO; GO:0016242; P:negative regulation of macroautophagy; ISS:ParkinsonsUK-UCL. DR GO; GO:0032007; P:negative regulation of TOR signaling; IDA:ComplexPortal. DR GO; GO:1904262; P:negative regulation of TORC1 signaling; IDA:UniProtKB. DR GO; GO:0017148; P:negative regulation of translation; IMP:UniProtKB. DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl. DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; IDA:UniProtKB. DR GO; GO:0006813; P:potassium ion transport; IEA:Ensembl. DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB. DR GO; GO:0051726; P:regulation of cell cycle; IBA:GO_Central. DR GO; GO:0001952; P:regulation of cell-matrix adhesion; IMP:UniProtKB. DR GO; GO:0043666; P:regulation of phosphoprotein phosphatase activity; IMP:UniProtKB. DR GO; GO:0051492; P:regulation of stress fiber assembly; IDA:UniProtKB. DR GO; GO:0006417; P:regulation of translation; IDA:UniProtKB. DR GO; GO:0032868; P:response to insulin; IDA:UniProtKB. DR GO; GO:0006407; P:rRNA export from nucleus; IMP:UniProtKB. DR GO; GO:0050808; P:synapse organization; IEA:Ensembl. DR DisProt; DP02744; -. DR InterPro; IPR007483; Hamartin. DR PANTHER; PTHR15154; HAMARTIN; 1. DR PANTHER; PTHR15154:SF2; HAMARTIN; 1. DR Pfam; PF04388; Hamartin; 1. DR Genevisible; Q92574; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Chaperone; Coiled coil; Cytoplasm; KW Disease variant; Epilepsy; Lysosome; Membrane; Phosphoprotein; KW Reference proteome; Tumor suppressor. FT CHAIN 1..1164 FT /note="Hamartin" FT /id="PRO_0000065651" FT REGION 403..787 FT /note="Mediates interaction with WDR45B" FT /evidence="ECO:0000269|PubMed:28561066" FT REGION 439..571 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1006..1085 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1131..1164 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 721..997 FT /evidence="ECO:0000255" FT COMPBIAS 468..484 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 512..534 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1017..1049 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1059..1084 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 487 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 505 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:15963462, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:23186163" FT MOD_RES 511 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 521 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 598 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 1100 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT VAR_SEQ 70..120 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_042890" FT VARIANT 22 FT /note="R -> W (in FCORD2; somatic mutation; decreased FT interaction with TSC2; decreased function in negative FT regulation of TOR signaling; dbSNP:rs749030456)" FT /evidence="ECO:0000269|PubMed:28215400" FT /id="VAR_078844" FT VARIANT 51 FT /note="E -> D (in TSC1; uncertain significance; FT dbSNP:rs118203342)" FT /id="VAR_009397" FT VARIANT 61 FT /note="L -> R (in TSC1; uncertain significance; reduced FT expression; altered subcellular localization; reduced FT inhibition of TORC1 signaling; dbSNP:rs118203345)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070636" FT VARIANT 68 FT /note="H -> R (in a bladder tumor; somatic mutation; FT reduced stability; does not affect interaction with TSC2; FT dbSNP:rs118203347)" FT /evidence="ECO:0000269|PubMed:18397877" FT /id="VAR_054386" FT VARIANT 72 FT /note="L -> P (in TSC1; dbSNP:rs118203354)" FT /evidence="ECO:0000269|PubMed:10533069" FT /id="VAR_054387" FT VARIANT 117 FT /note="L -> P (in TSC1; reduced expression; altered FT subcellular localization; reduced interaction with TSC2; FT reduced inhibition of TORC1 signaling; dbSNP:rs118203368)" FT /evidence="ECO:0000269|PubMed:18830229, FT ECO:0000269|PubMed:22161988, ECO:0000269|PubMed:29127155" FT /id="VAR_070637" FT VARIANT 126 FT /note="V -> I (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs397514843)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070638" FT VARIANT 128 FT /note="Missing (in TSC1; reduced expression; reduced FT inhibition of TORC1 signaling)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_070639" FT VARIANT 132 FT /note="G -> D (in TSC1; uncertain significance; reduced FT expression; altered subcellular localization; reduced FT inhibition of TORC1 signaling; dbSNP:rs397514784)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070640" FT VARIANT 133 FT /note="V -> I (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs118203381)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070641" FT VARIANT 158 FT /note="F -> C (in a bladder tumor; somatic mutation; FT reduced stability; does not affect interaction with TSC2; FT dbSNP:rs118203385)" FT /evidence="ECO:0000269|PubMed:18397877" FT /id="VAR_054388" FT VARIANT 158 FT /note="F -> S (found in a patient suspected of having FT tuberous sclerosis; uncertain significance; reduced FT expression; altered subcellular localization; reduced FT inhibition of TORC1 signaling; dbSNP:rs118203385)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070642" FT VARIANT 165..1164 FT /note="Missing (in TSC1)" FT /evidence="ECO:0000269|PubMed:11829138" FT /id="VAR_078845" FT VARIANT 180 FT /note="L -> P (in TSC1; reduced expression; reduced FT inhibition of TORC1 signaling; dbSNP:rs118203396)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_070643" FT VARIANT 190 FT /note="R -> S" FT /id="VAR_009398" FT VARIANT 191 FT /note="L -> H (in TSC1; reduced expression; reduced FT inhibition of TORC1 signaling; dbSNP:rs118203403)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_009399" FT VARIANT 198..199 FT /note="NF -> I (in TSC1; reduced expression; altered FT subcellular localization; reduced interaction with TSC2; FT reduced inhibition of TORC1 signaling)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_009400" FT VARIANT 204 FT /note="R -> C (in FCORD2; somatic mutation; decreased FT interaction with TSC2; decreased function in negative FT regulation of TOR signaling; dbSNP:rs1060505021)" FT /evidence="ECO:0000269|PubMed:28215400" FT /id="VAR_078846" FT VARIANT 204 FT /note="R -> P (found in a patient suspected of having FT tuberous sclerosis; reduced expression; altered subcellular FT localization; reduced inhibition of TORC1 signaling; FT dbSNP:rs397514834)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070644" FT VARIANT 206 FT /note="H -> D (in a bladder tumor; somatic mutation; FT reduced stability; does not affect interaction with TSC2)" FT /evidence="ECO:0000269|PubMed:18397877" FT /id="VAR_054389" FT VARIANT 216 FT /note="F -> L (in a bladder tumor; diffuse punctate FT cytoplasmic distribution in aminoacid-starved conditions; FT does not affect interaction with TSC2; dbSNP:rs1323541164)" FT /evidence="ECO:0000269|PubMed:18397877" FT /id="VAR_054390" FT VARIANT 224 FT /note="M -> R (in TSC1; reduced expression; reduced FT inhibition of TORC1 signaling; dbSNP:rs118203426)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_009401" FT VARIANT 246 FT /note="R -> K (in TSC1; uncertain significance; no effect FT on expression; no effect on inhibition of TORC1 signaling; FT dbSNP:rs118203436)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_070645" FT VARIANT 305 FT /note="G -> R (in TSC1; uncertain significance; no effect FT on expression; no effect on inhibition of TORC1 signaling; FT dbSNP:rs118203468)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_070646" FT VARIANT 305 FT /note="G -> W (in TSC1; uncertain significance; no effect FT on expression; no effect on inhibition of TORC1 signaling; FT dbSNP:rs118203468)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_070647" FT VARIANT 322 FT /note="M -> T (in dbSNP:rs1073123)" FT /evidence="ECO:0000269|PubMed:10533067, FT ECO:0000269|PubMed:10570911, ECO:0000269|PubMed:10607950, FT ECO:0000269|PubMed:9328481, ECO:0000269|PubMed:9924605" FT /id="VAR_009402" FT VARIANT 336 FT /note="R -> Q (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs397514808)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070648" FT VARIANT 362 FT /note="P -> S (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs397514864)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070649" FT VARIANT 411 FT /note="L -> I (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs397514840)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070650" FT VARIANT 417 FT /note="T -> I (in TSC1; uncertain significance; does not FT affect interaction with TSC2; dbSNP:rs77464996)" FT /evidence="ECO:0000269|PubMed:10570911, FT ECO:0000269|PubMed:10607950, ECO:0000269|PubMed:18397877" FT /id="VAR_009403" FT VARIANT 448 FT /note="P -> S (no effect on expression; no effect on FT subcellular localization; no effect on inhibition of TORC1 FT signaling; dbSNP:rs118203518)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070651" FT VARIANT 500 FT /note="R -> Q (in TSC1; dbSNP:rs118203538)" FT /evidence="ECO:0000269|PubMed:10874311" FT /id="VAR_054391" FT VARIANT 509 FT /note="R -> Q (no effect on expression; no effect on FT inhibition of TORC1 signaling; dbSNP:rs118203543)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_070652" FT VARIANT 523 FT /note="A -> P (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs118203548)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070653" FT VARIANT 567 FT /note="A -> V (no effect on expression; no effect on FT subcellular localization; no effect on inhibition of TORC1 FT signaling; dbSNP:rs397514880)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070654" FT VARIANT 577 FT /note="E -> D (in dbSNP:rs118203571)" FT /evidence="ECO:0000269|PubMed:10607950" FT /id="VAR_009404" FT VARIANT 586..589 FT /note="CKIP -> S (in TSC1)" FT /id="VAR_009405" FT VARIANT 587 FT /note="K -> R (in dbSNP:rs118203576)" FT /evidence="ECO:0000269|PubMed:9242607, FT ECO:0000269|PubMed:9924605" FT /id="VAR_009406" FT VARIANT 654 FT /note="Q -> E (in TSC1; dbSNP:rs75820036)" FT /evidence="ECO:0000269|PubMed:10570911" FT /id="VAR_009407" FT VARIANT 693 FT /note="D -> H (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs397514800)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070655" FT VARIANT 698 FT /note="L -> R (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs397514802)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070656" FT VARIANT 701 FT /note="Q -> H (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs118203639)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070657" FT VARIANT 726 FT /note="A -> E (in TSC1; dbSNP:rs118203655)" FT /evidence="ECO:0000269|PubMed:9328481" FT /id="VAR_009408" FT VARIANT 732 FT /note="H -> Y (in dbSNP:rs118203657)" FT /evidence="ECO:0000269|PubMed:10533067, FT ECO:0000269|PubMed:12112044, ECO:0000269|PubMed:9328481, FT ECO:0000269|PubMed:9924605" FT /id="VAR_009409" FT VARIANT 762 FT /note="N -> S (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs118203670)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070658" FT VARIANT 809 FT /note="E -> Q (in dbSNP:rs118203692)" FT /evidence="ECO:0000269|PubMed:10533067" FT /id="VAR_009410" FT VARIANT 811 FT /note="R -> G (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs397514814)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070659" FT VARIANT 829 FT /note="S -> R (in dbSNP:rs118203699)" FT /evidence="ECO:0000269|PubMed:10607950" FT /id="VAR_009411" FT VARIANT 883 FT /note="A -> T (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs118203721)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070660" FT VARIANT 899 FT /note="T -> S (in TSC1; dbSNP:rs76801599)" FT /evidence="ECO:0000269|PubMed:10570911" FT /id="VAR_009412" FT VARIANT 978 FT /note="L -> V (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs397514859)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070661" FT VARIANT 1035 FT /note="G -> S (no effect on expression; no effect on FT inhibition of TORC1 signaling; dbSNP:rs118203742)" FT /evidence="ECO:0000269|PubMed:18830229, FT ECO:0000269|PubMed:9328481, ECO:0000269|PubMed:9924605" FT /id="VAR_009413" FT VARIANT 1043 FT /note="Missing (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070662" FT VARIANT 1097 FT /note="R -> H (no effect on expression; no effect on FT inhibition of TORC1 signaling; dbSNP:rs118203750)" FT /evidence="ECO:0000269|PubMed:18830229" FT /id="VAR_070663" FT VARIANT 1108 FT /note="G -> S (in dbSNP:rs118203753)" FT /evidence="ECO:0000269|PubMed:9924605" FT /id="VAR_009414" FT VARIANT 1146 FT /note="D -> Y (in TSC1; uncertain significance; no effect FT on expression; no effect on subcellular localization; no FT effect on inhibition of TORC1 signaling; FT dbSNP:rs397514806)" FT /evidence="ECO:0000269|PubMed:22161988" FT /id="VAR_070664" FT MUTAGEN 941 FT /note="L->A: Abolished interaction with TBC1D7; when FT associated with 965-A--A-969." FT /evidence="ECO:0000269|PubMed:26893383" FT MUTAGEN 954..962 FT /note="ITQVFELEI->ATQVAELEA: Reduced interaction with FT TBC1D7 without affecting interaction with TSC2." FT /evidence="ECO:0000269|PubMed:26893383" FT MUTAGEN 954 FT /note="I->A: Abolished interaction with TBC1D7." FT /evidence="ECO:0000269|PubMed:26893383" FT MUTAGEN 958 FT /note="F->A: Abolished interaction with TBC1D7." FT /evidence="ECO:0000269|PubMed:26893383" FT MUTAGEN 962 FT /note="I->A: Abolished interaction with TBC1D7." FT /evidence="ECO:0000269|PubMed:26893383" FT MUTAGEN 965..969 FT /note="LYGRL->AAGRA: Slightly reduced interaction with FT TBC1D7 without affecting interaction with TSC2." FT /evidence="ECO:0000269|PubMed:26893383" FT HELIX 941..971 FT /evidence="ECO:0007829|PDB:4Z6Y" FT HELIX 975..991 FT /evidence="ECO:0007829|PDB:4Z6Y" SQ SEQUENCE 1164 AA; 129767 MW; EF15509385C7AACC CRC64; MAQQANVGEL LAMLDSPMLG VRDDVTAVFK ENLNSDRGPM LVNTLVDYYL ETSSQPALHI LTTLQEPHDK HLLDRINEYV GKAATRLSIL SLLGHVIRLQ PSWKHKLSQA PLLPSLLKCL KMDTDVVVLT TGVLVLITML PMIPQSGKQH LLDFFDIFGR LSSWCLKKPG HVAEVYLVHL HASVYALFHR LYGMYPCNFV SFLRSHYSMK ENLETFEEVV KPMMEHVRIH PELVTGSKDH ELDPRRWKRL ETHDVVIECA KISLDPTEAS YEDGYSVSHQ ISARFPHRSA DVTTSPYADT QNSYGCATST PYSTSRLMLL NMPGQLPQTL SSPSTRLITE PPQATLWSPS MVCGMTTPPT SPGNVPPDLS HPYSKVFGTT AGGKGTPLGT PATSPPPAPL CHSDDYVHIS LPQATVTPPR KEERMDSARP CLHRQHHLLN DRGSEEPPGS KGSVTLSDLP GFLGDLASEE DSIEKDKEEA AISRELSEIT TAEAEPVVPR GGFDSPFYRD SLPGSQRKTH SAASSSQGAS VNPEPLHSSL DKLGPDTPKQ AFTPIDLPCG SADESPAGDR ECQTSLETSI FTPSPCKIPP PTRVGFGSGQ PPPYDHLFEV ALPKTAHHFV IRKTEELLKK AKGNTEEDGV PSTSPMEVLD RLIQQGADAH SKELNKLPLP SKSVDWTHFG GSPPSDEIRT LRDQLLLLHN QLLYERFKRQ QHALRNRRLL RKVIKAAALE EHNAAMKDQL KLQEKDIQMW KVSLQKEQAR YNQLQEQRDT MVTKLHSQIR QLQHDREEFY NQSQELQTKL EDCRNMIAEL RIELKKANNK VCHTELLLSQ VSQKLSNSES VQQQMEFLNR QLLVLGEVNE LYLEQLQNKH SDTTKEVEMM KAAYRKELEK NRSHVLQQTQ RLDTSQKRIL ELESHLAKKD HLLLEQKKYL EDVKLQARGQ LQAAESRYEA QKRITQVFEL EILDLYGRLE KDGLLKKLEE EKAEAAEAAE ERLDCCNDGC SDSMVGHNEE ASGHNGETKT PRPSSARGSS GSRGGGGSSS SSSELSTPEK PPHQRAGPFS SRWETTMGEA SASIPTTVGS LPSSKSFLGM KARELFRNKS ESQCDEDGMT SSLSESLKTE LGKDLGVEAK IPLNLDGPHP SPPTPDSVGQ LHIMDYNETH HEHS //