ID RHEB_HUMAN Reviewed; 184 AA. AC Q15382; B3KWN6; D3DX13; Q53Y56; Q99444; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 234. DE RecName: Full=GTP-binding protein Rheb {ECO:0000305}; DE AltName: Full=Ras homolog enriched in brain; DE EC=3.6.5.- {ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:22819219}; DE Flags: Precursor; GN Name=RHEB {ECO:0000303|PubMed:8543055, ECO:0000312|HGNC:HGNC:10011}; GN Synonyms=RHEB2; 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], AND TISSUE SPECIFICITY. RC TISSUE=Psoriatic skin; RX PubMed=8543055; DOI=10.1016/0014-5793(95)01349-0; RA Gromov P.S., Madsen P., Tomerup N., Celis J.E.; RT "A novel approach for expression cloning of small GTPases: identification, RT tissue distribution and chromosome mapping of the human homolog of rheb."; RL FEBS Lett. 377:221-226(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Skin; RX PubMed=8661031; DOI=10.1006/geno.1996.0248; RA Mizuki N., Kimura M., Ohno S., Miyata S., Sato M., Ando H., Ishihara M., RA Goto K., Watanabe S., Yamazaki M., Ono A., Taguchi S., Okumura K., RA Nogami M., Taguchi H., Ando A., Inoko H.; RT "Isolation of cDNA and genomic clones of a human Ras-related GTP-binding RT protein gene and its chromosomal localization to the long arm of chromosome RT 7, 7q36."; RL Genomics 34:114-118(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Mammary carcinoma; RA Weidenmueller U., Tur M.K., Tawadros S., Engert A., Barth S.; RT "Detection of membrane-associated proteins using serum of mice immunized RT with membrane fractions of breast carcinoma cells."; RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.; RT "cDNA clones of human proteins involved in signal transduction sequenced by RT the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H., RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., RA Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [8] 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 [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Muscle, and Testis; 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 [10] RP FUNCTION. 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, ACTIVITY REGULATION, ISOPRENYLATION AT CYS-181, AND MUTAGENESIS RP OF CYS-181. 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 FUNCTION, AND ACTIVITY REGULATION. 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 [13] RP FUNCTION, ACTIVITY REGULATION, ISOPRENYLATION, AND MUTAGENESIS OF GLN-64. RX PubMed=12842888; DOI=10.1074/jbc.c300226200; RA Castro A.F., Rebhun J.F., Clark G.J., Quilliam L.A.; RT "Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase RT activation in a rapamycin- and farnesylation-dependent manner."; RL J. Biol. Chem. 278:32493-32496(2003). RN [14] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=12869586; DOI=10.1101/gad.1110003; RA Inoki K., Li Y., Xu T., Guan K.-L.; RT "Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR RT signaling."; RL Genes Dev. 17:1829-1834(2003). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF RP ARG-15; SER-20; ASP-60; GLN-64 AND CYS-181. 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 [16] RP ISOPRENYLATION AT CYS-181. RX PubMed=15308774; DOI=10.1073/pnas.0403413101; RA Kho Y., Kim S.C., Jiang C., Barma D., Kwon S.W., Cheng J., Jaunbergs J., RA Weinbaum C., Tamanoi F., Falck J., Zhao Y.; RT "A tagging-via-substrate technology for detection and proteomics of RT farnesylated proteins."; RL Proc. Natl. Acad. Sci. U.S.A. 101:12479-12484(2004). RN [17] RP FUNCTION, INTERACTION WITH MTOR; MLST8; RPTOR AND TSC2, AND MUTAGENESIS OF RP SER-20; THR-38; ILE-39 AND ASN-41. RX PubMed=15854902; DOI=10.1016/j.cub.2005.02.053; RA Long X., Lin Y., Ortiz-Vega S., Yonezawa K., Avruch J.; RT "Rheb binds and regulates the mTOR kinase."; RL Curr. Biol. 15:702-713(2005). RN [18] RP FUNCTION, MUTAGENESIS OF THR-38; GLU-40; ASN-41; PHE-43; LEU-46; THR-48; RP VAL-49; GLU-53; TYR-54 AND LEU-56, AND INTERACTION WITH MTOR. RX PubMed=16098514; DOI=10.1016/j.febslet.2005.07.054; RA Tee A.R., Blenis J., Proud C.G.; RT "Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1."; RL FEBS Lett. 579:4763-4768(2005). RN [19] RP FUNCTION. RX PubMed=20381137; DOI=10.1016/j.cell.2010.02.024; RA Sancak Y., Bar-Peled L., Zoncu R., Markhard A.L., Nada S., Sabatini D.M.; RT "Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is RT necessary for its activation by amino acids."; RL Cell 141:290-303(2010). RN [20] 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 [21] RP FUNCTION, ACTIVITY REGULATION, 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 [22] RP UBIQUITINATION AT LYS-8, DEUBIQUITINATION, AND MUTAGENESIS OF LYS-8. RX PubMed=30514904; DOI=10.1038/s41422-018-0120-9; RA Deng L., Chen L., Zhao L., Xu Y., Peng X., Wang X., Ding L., Jin J., RA Teng H., Wang Y., Pan W., Yu F., Liao L., Li L., Ge X., Wang P.; RT "Ubiquitination of Rheb governs growth factor-induced mTORC1 activation."; RL Cell Res. 29:136-150(2019). RN [23] RP FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, DEUBIQUITINATION BY ATXN3, RP AND MUTAGENESIS OF LYS-8; LYS-109; LYS-135; LYS-151 AND LYS-178. RX PubMed=33157014; DOI=10.1016/j.molcel.2020.10.004; RA Yao Y., Hong S., Ikeda T., Mori H., MacDougald O.A., Nada S., Okada M., RA Inoki K.; RT "Amino acids enhance polyubiquitination of Rheb and its binding to mTORC1 RT by blocking lysosomal ATXN3 deubiquitinase activity."; RL Mol. Cell 80:437-451(2020). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-169 IN COMPLEX WITH MAGNESIUM; RP GDP AND GTP. RX PubMed=15728574; DOI=10.1074/jbc.m501253200; RA Yu Y., Li S., Xu X., Li Y., Guan K., Arnold E., Ding J.; RT "Structural basis for the unique biological function of small GTPase RT RHEB."; RL J. Biol. Chem. 280:17093-17100(2005). RN [25] {ECO:0007744|PDB:3T5G} RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1-181 IN COMPLEX WITH GDP AND RP PDE6D, ISOPRENYLATION AT CYS-181, METHYLATION AT CYS-181, INTERACTION WITH RP PDE6D, AND SUBCELLULAR LOCATION. RX PubMed=22002721; DOI=10.1038/nchembio.686; RA Ismail S.A., Chen Y.X., Rusinova A., Chandra A., Bierbaum M., Gremer L., RA Triola G., Waldmann H., Bastiaens P.I., Wittinghofer A.; RT "Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for RT farnesylated cargo."; RL Nat. Chem. Biol. 7:942-949(2011). RN [26] {ECO:0007744|PDB:3SEA} RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 3-169 IN COMPLEX WITH GDP, RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH TSC2, RP AND MUTAGENESIS OF TYR-35; ASP-60 AND ASP-65. RX PubMed=22819219; DOI=10.1016/j.str.2012.06.013; RA Mazhab-Jafari M.T., Marshall C.B., Ishiyama N., Ho J., Di Palma V., RA Stambolic V., Ikura M.; RT "An autoinhibited noncanonical mechanism of GTP hydrolysis by Rheb RT maintains mTORC1 homeostasis."; RL Structure 20:1528-1539(2012). RN [27] {ECO:0007744|PDB:6BCU} RP STRUCTURE BY ELECTRON MICROSCOPY (3.43 ANGSTROMS) IN COMPLEX WITH RP MAGNESIUM; GTP; MLST8; MTOR; RPTOR AND EIF4EBP1, AND FUNCTION. RX PubMed=29236692; DOI=10.1038/nature25023; RA Yang H., Jiang X., Li B., Yang H.J., Miller M., Yang A., Dhar A., RA Pavletich N.P.; RT "Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40."; RL Nature 552:368-373(2017). RN [28] {ECO:0007744|PDB:5YXH, ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0} RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 1-169 IN COMPLEX WITH GDP AND RP MAGNESIUM, FUNCTION, AND ACTIVITY REGULATION. RX PubMed=29416044; DOI=10.1038/s41467-018-03035-z; RA Mahoney S.J., Narayan S., Molz L., Berstler L.A., Kang S.A., Vlasuk G.P., RA Saiah E.; RT "A small molecule inhibitor of Rheb selectively targets mTORC1 signaling."; RL Nat. Commun. 9:548-548(2018). RN [29] {ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC, ECO:0007744|PDB:7BTD} RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 1-169 IN COMPLEX WITH GDP AND GTP RP ANALOG, FUNCTION, AND MUTAGENESIS OF TYR-35 AND ASP-60. RX PubMed=32470140; DOI=10.1093/jmcb/mjaa025; RA Zhang C., Liu Y., Zhang Y., Wang X., Zhang T., Ding J.; RT "Molecular basis for the functions of dominantly active Y35N and inactive RT D60K Rheb mutants in mTORC1 signaling."; RL J. Mol. Cell Biol. 12:741-744(2020). RN [30] RP VARIANT [LARGE SCALE ANALYSIS] LYS-139. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Small GTPase that acts as an allosteric activator of the CC canonical mTORC1 complex, an evolutionarily conserved central nutrient CC sensor that stimulates anabolic reactions and macromolecule CC biosynthesis to promote cellular biomass generation and growth CC (PubMed:12172553, PubMed:12906785, PubMed:12271141, PubMed:12842888, CC PubMed:12869586, PubMed:15340059, PubMed:15854902, PubMed:16098514, CC PubMed:20381137, PubMed:24529379, PubMed:22819219, PubMed:29416044, CC PubMed:32470140, PubMed:33157014). In response to nutrients, growth CC factors or amino acids, specifically activates the protein kinase CC activity of MTOR, the catalytic component of the mTORC1 complex: acts CC by causing a conformational change that allows the alignment of CC residues in the active site of MTOR, thereby enhancing the CC phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) CC and EIF4EBP1 (4E-BP1) (PubMed:33157014, PubMed:29236692). RHEB is also CC required for localization of the TSC-TBC complex to lysosomal membranes CC (PubMed:24529379). In response to starvation, RHEB is inactivated by CC the TSC-TBC complex, preventing activation of mTORC1 (PubMed:24529379, CC PubMed:33157014). Has low intrinsic GTPase activity (PubMed:15340059). CC {ECO:0000269|PubMed:12172553, ECO:0000269|PubMed:12271141, CC ECO:0000269|PubMed:12842888, ECO:0000269|PubMed:12869586, CC ECO:0000269|PubMed:12906785, ECO:0000269|PubMed:15340059, CC ECO:0000269|PubMed:15854902, ECO:0000269|PubMed:16098514, CC ECO:0000269|PubMed:20381137, ECO:0000269|PubMed:22819219, CC ECO:0000269|PubMed:24529379, ECO:0000269|PubMed:29236692, CC ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, CC ECO:0000269|PubMed:33157014}. CC -!- CATALYTIC ACTIVITY: CC Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; CC Evidence={ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:22819219}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19670; CC Evidence={ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:22819219}; CC -!- ACTIVITY REGULATION: Alternates between an inactive form bound to GDP CC and an active form bound to GTP (PubMed:12906785, PubMed:12271141, CC PubMed:12842888, PubMed:12869586, PubMed:15340059, PubMed:24529379, CC PubMed:22819219). Inactivated by the TSC-TBC complex via the GTPase CC activating protein (GAP) domain of TSC2 (PubMed:12906785, CC PubMed:12271141, PubMed:12842888, PubMed:12869586, PubMed:15340059, CC PubMed:24529379, PubMed:22819219). Autoinhibited by Tyr-35, which CC constrains the active site conformation, restricting the access of the CC catalytic Asp-65 to the nucleotide-binding pocket (PubMed:22819219). CC Specifically inhibited by NR1 (4-bromo-6-(3,4-dichlorophenylthio)-1-(4- CC (dimethylcarbamoyl)benzyl)-1H-indole-2-carboxylic acid) CC (PubMed:29416044). {ECO:0000269|PubMed:12271141, CC ECO:0000269|PubMed:12842888, ECO:0000269|PubMed:12869586, CC ECO:0000269|PubMed:12906785, ECO:0000269|PubMed:15340059, CC ECO:0000269|PubMed:22819219, ECO:0000269|PubMed:24529379, CC ECO:0000269|PubMed:29416044}. CC -!- SUBUNIT: Associates with the mTORC1 complex (MTOR, MLST8 and RPTOR) in CC a guanyl nucleotide-independent manner (PubMed:15854902, CC PubMed:16098514, PubMed:24529379). Interacts with TSC2 CC (PubMed:15854902, PubMed:24529379, PubMed:22819219). Interacts (when CC prenylated) with PDE6D; this promotes release from membranes CC (PubMed:22002721). {ECO:0000269|PubMed:15854902, CC ECO:0000269|PubMed:16098514, ECO:0000269|PubMed:22002721, CC ECO:0000269|PubMed:22819219, ECO:0000269|PubMed:24529379}. CC -!- INTERACTION: CC Q15382; Q92624: APPBP2; NbExp=3; IntAct=EBI-1055287, EBI-743771; CC Q15382; P55212: CASP6; NbExp=3; IntAct=EBI-1055287, EBI-718729; CC Q15382; P06307: CCK; NbExp=3; IntAct=EBI-1055287, EBI-6624398; CC Q15382; P22607: FGFR3; NbExp=3; IntAct=EBI-1055287, EBI-348399; CC Q15382; Q14957: GRIN2C; NbExp=3; IntAct=EBI-1055287, EBI-8285963; CC Q15382; O00291: HIP1; NbExp=3; IntAct=EBI-1055287, EBI-473886; CC Q15382; P13473-2: LAMP2; NbExp=4; IntAct=EBI-1055287, EBI-21591415; CC Q15382; P42345: MTOR; NbExp=2; IntAct=EBI-1055287, EBI-359260; CC Q15382; Q13393: PLD1; NbExp=2; IntAct=EBI-1055287, EBI-2827556; CC Q15382; O75400-2: PRPF40A; NbExp=3; IntAct=EBI-1055287, EBI-5280197; CC Q15382; P62826: RAN; NbExp=3; IntAct=EBI-1055287, EBI-286642; CC Q15382; P13693: TPT1; NbExp=2; IntAct=EBI-1055287, EBI-1783169; CC Q15382; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-1055287, EBI-741480; CC Q15382; Q9Y649; NbExp=3; IntAct=EBI-1055287, EBI-25900580; CC PRO_0000082708; O43924: PDE6D; NbExp=5; IntAct=EBI-6860739, EBI-712685; CC -!- SUBCELLULAR LOCATION: Endomembrane system CC {ECO:0000269|PubMed:22002721}; Lipid-anchor CC {ECO:0000269|PubMed:22002721}; Cytoplasmic side CC {ECO:0000269|PubMed:15489334}. Lysosome membrane CC {ECO:0000269|PubMed:24529379, ECO:0000269|PubMed:33157014}; Lipid- CC anchor {ECO:0000269|PubMed:22002721}; Cytoplasmic side CC {ECO:0000269|PubMed:15489334}. Golgi apparatus membrane CC {ECO:0000269|PubMed:22002721}; Lipid-anchor CC {ECO:0000305|PubMed:22002721}; Cytoplasmic side CC {ECO:0000305|PubMed:22002721}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:22002721}; Lipid-anchor CC {ECO:0000269|PubMed:22002721}; Cytoplasmic side CC {ECO:0000269|PubMed:22002721}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:22002721}. Note=Farnesylation is required for CC recruitment to lysosomal membranes, where it activates the mTORC1 CC complex. {ECO:0000269|PubMed:24529379}. CC -!- TISSUE SPECIFICITY: Ubiquitous (PubMed:8543055). Highest levels CC observed in skeletal and cardiac muscle (PubMed:8543055). CC {ECO:0000269|PubMed:8543055}. CC -!- PTM: Farnesylation is important for efficiently activating mTORC1- CC mediated signaling. {ECO:0000269|PubMed:12842888, CC ECO:0000269|PubMed:12906785, ECO:0000269|PubMed:22002721}. CC -!- PTM: Polyubiquitinated in response to amino acid, promoting its CC interaction with MTOR and mTORC1 activation (PubMed:33157014). CC Deubiquitination by ATXN3 promotes recruitment of the TSC-TBC complex CC and RHEB inactivation by TSC2 (PubMed:33157014). Monoubiquitinated at CC Lys-8 by RNF152, promoting its association with the TSC-TBC complex CC (PubMed:30514904). Deubiquitinated at Lys-8 by USP4, promoting mTORC1 CC activation (PubMed:30514904). {ECO:0000269|PubMed:30514904, CC ECO:0000269|PubMed:33157014}. CC -!- PTM: Phosphorylation by MAPKAPK5 impairs GTP-binding and inactivation. CC {ECO:0000250|UniProtKB:Q921J2}. CC -!- MISCELLANEOUS: The conserved catalytic Gln-64 found in other Ras-like CC GTPases seems not to be involved in GTP hydrolysis in RHEB. CC {ECO:0000269|PubMed:15340059}. CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Rheb family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Z29677; CAA82774.1; -; mRNA. DR EMBL; D78132; BAA11211.1; -; mRNA. DR EMBL; AF148645; AAF73125.1; -; mRNA. DR EMBL; AF493921; AAM12635.1; -; mRNA. DR EMBL; AK125446; BAG54198.1; -; mRNA. DR EMBL; BT006958; AAP35604.1; -; mRNA. DR EMBL; AC005996; AAD15548.1; -; Genomic_DNA. DR EMBL; CH471173; EAW53989.1; -; Genomic_DNA. DR EMBL; BC016155; AAH16155.1; -; mRNA. DR EMBL; BC107705; AAI07706.1; -; mRNA. DR CCDS; CCDS5927.1; -. DR PIR; S68419; S41960. DR RefSeq; NP_005605.1; NM_005614.3. DR PDB; 1XTQ; X-ray; 2.00 A; A=1-169. DR PDB; 1XTR; X-ray; 2.65 A; A=1-169. DR PDB; 1XTS; X-ray; 2.80 A; A=1-169. DR PDB; 3SEA; X-ray; 2.00 A; A/B=3-169. DR PDB; 3T5G; X-ray; 1.70 A; A=1-181. DR PDB; 5YXH; X-ray; 2.04 A; A/B/C/D=2-169. DR PDB; 6BCU; EM; 3.43 A; R/S=1-184. DR PDB; 6BSX; X-ray; 1.65 A; A/B/C/D=1-169. DR PDB; 6BT0; X-ray; 2.60 A; A/B/C/D=1-169. DR PDB; 7BTA; X-ray; 2.60 A; A/B=1-169. DR PDB; 7BTC; X-ray; 2.10 A; A/B/C/D=1-169. DR PDB; 7BTD; X-ray; 2.00 A; A=1-169. DR PDBsum; 1XTQ; -. DR PDBsum; 1XTR; -. DR PDBsum; 1XTS; -. DR PDBsum; 3SEA; -. DR PDBsum; 3T5G; -. DR PDBsum; 5YXH; -. DR PDBsum; 6BCU; -. DR PDBsum; 6BSX; -. DR PDBsum; 6BT0; -. DR PDBsum; 7BTA; -. DR PDBsum; 7BTC; -. DR PDBsum; 7BTD; -. DR AlphaFoldDB; Q15382; -. DR BMRB; Q15382; -. DR EMDB; EMD-7086; -. DR SMR; Q15382; -. DR BioGRID; 111941; 104. DR DIP; DIP-42816N; -. DR IntAct; Q15382; 51. DR MINT; Q15382; -. DR STRING; 9606.ENSP00000262187; -. DR BindingDB; Q15382; -. DR ChEMBL; CHEMBL3108656; -. DR DrugBank; DB04315; Guanosine-5'-Diphosphate. DR DrugBank; DB04137; Guanosine-5'-Triphosphate. DR iPTMnet; Q15382; -. DR MetOSite; Q15382; -. DR PhosphoSitePlus; Q15382; -. DR SwissPalm; Q15382; -. DR BioMuta; RHEB; -. DR DMDM; 6919957; -. DR EPD; Q15382; -. DR jPOST; Q15382; -. DR MassIVE; Q15382; -. DR MaxQB; Q15382; -. DR PaxDb; 9606-ENSP00000262187; -. DR PeptideAtlas; Q15382; -. DR ProteomicsDB; 60554; -. DR Pumba; Q15382; -. DR TopDownProteomics; Q15382; -. DR Antibodypedia; 18765; 541 antibodies from 40 providers. DR DNASU; 6009; -. DR Ensembl; ENST00000262187.10; ENSP00000262187.5; ENSG00000106615.10. DR GeneID; 6009; -. DR KEGG; hsa:6009; -. DR MANE-Select; ENST00000262187.10; ENSP00000262187.5; NM_005614.4; NP_005605.1. DR UCSC; uc003wkh.1; human. DR AGR; HGNC:10011; -. DR CTD; 6009; -. DR DisGeNET; 6009; -. DR GeneCards; RHEB; -. DR HGNC; HGNC:10011; RHEB. DR HPA; ENSG00000106615; Low tissue specificity. DR MIM; 601293; gene. DR neXtProt; NX_Q15382; -. DR OpenTargets; ENSG00000106615; -. DR PharmGKB; PA34389; -. DR VEuPathDB; HostDB:ENSG00000106615; -. DR eggNOG; KOG0395; Eukaryota. DR GeneTree; ENSGT00940000159945; -. DR HOGENOM; CLU_041217_9_8_1; -. DR InParanoid; Q15382; -. DR OMA; SARHNEN; -. DR OrthoDB; 8685at2759; -. DR PhylomeDB; Q15382; -. DR TreeFam; TF314986; -. DR BRENDA; 3.6.5.2; 2681. DR PathwayCommons; Q15382; -. DR Reactome; R-HSA-1632852; Macroautophagy. DR Reactome; R-HSA-165159; MTOR signalling. DR Reactome; R-HSA-166208; mTORC1-mediated signalling. 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-8943724; Regulation of PTEN gene transcription. DR Reactome; R-HSA-9639288; Amino acids regulate mTORC1. DR SABIO-RK; Q15382; -. DR SignaLink; Q15382; -. DR SIGNOR; Q15382; -. DR BioGRID-ORCS; 6009; 537 hits in 1131 CRISPR screens. DR ChiTaRS; RHEB; human. DR EvolutionaryTrace; Q15382; -. DR GeneWiki; RHEB; -. DR GenomeRNAi; 6009; -. DR Pharos; Q15382; Tbio. DR PRO; PR:Q15382; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; Q15382; Protein. DR Bgee; ENSG00000106615; Expressed in ventricular zone and 143 other cell types or tissues. DR ExpressionAtlas; Q15382; baseline and differential. DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell. DR GO; GO:0012505; C:endomembrane system; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0014069; C:postsynaptic density; IDA:SynGO. DR GO; GO:0005681; C:spliceosomal complex; IEA:Ensembl. DR GO; GO:0019003; F:GDP binding; IMP:CAFA. DR GO; GO:0005525; F:GTP binding; IMP:CAFA. DR GO; GO:0003924; F:GTPase activity; IDA:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IMP:CAFA. DR GO; GO:0030295; F:protein kinase activator activity; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl. DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProt. DR GO; GO:0031669; P:cellular response to nutrient levels; IDA:UniProt. DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:0048709; P:oligodendrocyte differentiation; IEA:Ensembl. DR GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; IEA:Ensembl. DR GO; GO:0032008; P:positive regulation of TOR signaling; IMP:UniProtKB. DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IDA:UniProtKB. DR GO; GO:0051726; P:regulation of cell cycle; TAS:Reactome. DR GO; GO:0016241; P:regulation of macroautophagy; TAS:Reactome. DR GO; GO:2000074; P:regulation of type B pancreatic cell development; IMP:CACAO. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0007264; P:small GTPase mediated signal transduction; IBA:GO_Central. DR CDD; cd04137; RheB; 1. DR DisProt; DP00364; -. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR005225; Small_GTP-bd_dom. DR InterPro; IPR001806; Small_GTPase. DR InterPro; IPR020849; Small_GTPase_Ras-type. DR NCBIfam; TIGR00231; small_GTP; 1. DR PANTHER; PTHR24070:SF264; GTP-BINDING PROTEIN RHEB; 1. DR PANTHER; PTHR24070; RAS, DI-RAS, AND RHEB FAMILY MEMBERS OF SMALL GTPASE SUPERFAMILY; 1. DR Pfam; PF00071; Ras; 1. DR PRINTS; PR00449; RASTRNSFRMNG. DR SMART; SM00175; RAB; 1. DR SMART; SM00173; RAS; 1. DR SMART; SM00174; RHO; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51421; RAS; 1. DR Genevisible; Q15382; HS. PE 1: Evidence at protein level; KW 3D-structure; Cytoplasm; Endoplasmic reticulum; Golgi apparatus; KW GTP-binding; Hydrolase; Isopeptide bond; Lipoprotein; Lysosome; Magnesium; KW Membrane; Metal-binding; Methylation; Nucleotide-binding; Phosphoprotein; KW Prenylation; Reference proteome; Ubl conjugation. FT CHAIN 1..181 FT /note="GTP-binding protein Rheb" FT /id="PRO_0000082708" FT PROPEP 182..184 FT /note="Removed in mature form" FT /evidence="ECO:0000269|PubMed:15308774, FT ECO:0000269|PubMed:22002721" FT /id="PRO_0000281365" FT MOTIF 35..43 FT /note="Effector region" FT /evidence="ECO:0000305" FT BINDING 16 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, FT ECO:0007744|PDB:1XTQ, ECO:0007744|PDB:3SEA, FT ECO:0007744|PDB:3T5G, ECO:0007744|PDB:5YXH, FT ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 16 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0007744|PDB:1XTS, FT ECO:0007744|PDB:6BCU" FT BINDING 17 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:32470140, ECO:0007744|PDB:1XTQ, FT ECO:0007744|PDB:3SEA, ECO:0007744|PDB:3T5G, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 18 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, FT ECO:0007744|PDB:1XTQ, ECO:0007744|PDB:3SEA, FT ECO:0007744|PDB:3T5G, ECO:0007744|PDB:5YXH, FT ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 18 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0007744|PDB:1XTS, FT ECO:0007744|PDB:6BCU" FT BINDING 19 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, FT ECO:0007744|PDB:1XTQ, ECO:0007744|PDB:3SEA, FT ECO:0007744|PDB:3T5G, ECO:0007744|PDB:5YXH, FT ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 19 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:29236692, FT ECO:0007744|PDB:1XTS, ECO:0007744|PDB:6BCU" FT BINDING 20 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, FT ECO:0007744|PDB:1XTQ, ECO:0007744|PDB:3SEA, FT ECO:0007744|PDB:3T5G, ECO:0007744|PDB:5YXH, FT ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 20 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0007744|PDB:1XTS, FT ECO:0007744|PDB:6BCU" FT BINDING 20 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0000269|PubMed:29416044, FT ECO:0007744|PDB:5YXH, ECO:0007744|PDB:6BCU, FT ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0" FT BINDING 21 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, FT ECO:0007744|PDB:1XTQ, ECO:0007744|PDB:3SEA, FT ECO:0007744|PDB:3T5G, ECO:0007744|PDB:5YXH, FT ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 21 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0007744|PDB:1XTS" FT BINDING 32 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0007744|PDB:3SEA, FT ECO:0007744|PDB:5YXH, ECO:0007744|PDB:6BSX" FT BINDING 32 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0007744|PDB:1XTS" FT BINDING 33 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, FT ECO:0007744|PDB:3SEA, ECO:0007744|PDB:6BT0, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 35 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0007744|PDB:1XTS, FT ECO:0007744|PDB:6BCU" FT BINDING 38 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0007744|PDB:1XTS, FT ECO:0007744|PDB:6BCU" FT BINDING 38 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0007744|PDB:6BCU" FT BINDING 119 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, FT ECO:0007744|PDB:1XTQ, ECO:0007744|PDB:3SEA, FT ECO:0007744|PDB:3T5G, ECO:0007744|PDB:5YXH, FT ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 119 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0007744|PDB:1XTS, FT ECO:0007744|PDB:6BCU" FT BINDING 122 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, FT ECO:0007744|PDB:1XTQ, ECO:0007744|PDB:3SEA, FT ECO:0007744|PDB:3T5G, ECO:0007744|PDB:5YXH, FT ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 122 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0007744|PDB:1XTS, FT ECO:0007744|PDB:6BCU" FT BINDING 150 FT /ligand="GDP" FT /ligand_id="ChEBI:CHEBI:58189" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:22002721, ECO:0000269|PubMed:22819219, FT ECO:0000269|PubMed:29416044, ECO:0000269|PubMed:32470140, FT ECO:0007744|PDB:1XTQ, ECO:0007744|PDB:3SEA, FT ECO:0007744|PDB:3T5G, ECO:0007744|PDB:5YXH, FT ECO:0007744|PDB:6BSX, ECO:0007744|PDB:6BT0, FT ECO:0007744|PDB:7BTA, ECO:0007744|PDB:7BTC" FT BINDING 150 FT /ligand="GTP" FT /ligand_id="ChEBI:CHEBI:37565" FT /evidence="ECO:0000269|PubMed:15728574, FT ECO:0000269|PubMed:29236692, ECO:0007744|PDB:1XTS, FT ECO:0007744|PDB:6BCU" FT SITE 35 FT /note="Important for autoinhibition of GTPase activity" FT /evidence="ECO:0000269|PubMed:22819219" FT MOD_RES 130 FT /note="Phosphoserine; by MAPKAPK5" FT /evidence="ECO:0000250|UniProtKB:Q921J2" FT MOD_RES 181 FT /note="Cysteine methyl ester" FT /evidence="ECO:0000269|PubMed:12906785, FT ECO:0000269|PubMed:15308774, ECO:0000269|PubMed:22002721, FT ECO:0007744|PDB:3T5G" FT LIPID 181 FT /note="S-farnesyl cysteine" FT /evidence="ECO:0000269|PubMed:12906785, FT ECO:0000269|PubMed:15308774, ECO:0000269|PubMed:22002721, FT ECO:0007744|PDB:3T5G" FT CROSSLNK 8 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:30514904" FT VARIANT 139 FT /note="E -> K (in a colorectal cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036310" FT MUTAGEN 8 FT /note="K->R: Decreased ubiquitination by RNF152. Does not FT affect polyubiquitination in response to amino acids." FT /evidence="ECO:0000269|PubMed:33157014" FT MUTAGEN 15 FT /note="R->G: Partially resistant to inactivation by FT TSC1-TSC2." FT /evidence="ECO:0000269|PubMed:15340059" FT MUTAGEN 20 FT /note="S->N: Deficient in guanine nucleotide binding. FT Unable to rescue RPS6KB1 from inactivation by amino-acid FT withdrawal." FT /evidence="ECO:0000269|PubMed:15340059, FT ECO:0000269|PubMed:15854902" FT MUTAGEN 35 FT /note="Y->A: Increased GTPase ativity; insensitive to TSC2 FT regulation, leading to impaired regulation of mTORC1 FT signaling." FT /evidence="ECO:0000269|PubMed:22819219" FT MUTAGEN 35 FT /note="Y->N: Dominant mutant, which can activate mTORC1 in FT both GDP- and GTP-bound forms." FT /evidence="ECO:0000269|PubMed:32470140" FT MUTAGEN 38 FT /note="T->M: Slightly impairs signaling through mTORC1, but FT still binds guanine nucleotides normally." FT /evidence="ECO:0000269|PubMed:15854902, FT ECO:0000269|PubMed:16098514" FT MUTAGEN 39 FT /note="I->K: Impairs RPS6KB1 activation, but still binds FT guanine nucleotides normally." FT /evidence="ECO:0000269|PubMed:15854902" FT MUTAGEN 40 FT /note="E->G: No effect." FT /evidence="ECO:0000269|PubMed:16098514" FT MUTAGEN 41 FT /note="N->A: Impairs interaction with MTOR. Impairs FT signaling through mTORC1, but still binds guanine FT nucleotides normally." FT /evidence="ECO:0000269|PubMed:15854902, FT ECO:0000269|PubMed:16098514" FT MUTAGEN 43 FT /note="F->C: No effect." FT /evidence="ECO:0000269|PubMed:16098514" FT MUTAGEN 46 FT /note="L->A: Causes slight reduction in RPS6KB1 FT activation." FT /evidence="ECO:0000269|PubMed:16098514" FT MUTAGEN 48 FT /note="T->A: Causes slightly reduced phosphorylation of FT EIF4EBP1." FT /evidence="ECO:0000269|PubMed:16098514" FT MUTAGEN 49 FT /note="V->A: Causes slightly reduced phosphorylation of FT EIF4EBP1." FT /evidence="ECO:0000269|PubMed:16098514" FT MUTAGEN 53 FT /note="E->A: Causes slightly reduced phosphorylation of FT EIF4EBP1." FT /evidence="ECO:0000269|PubMed:16098514" FT MUTAGEN 54 FT /note="Y->A: Partially deficient in guanine nucleotide FT binding. Fully impairs EIF4EBP1 phosphorylation and RPS6KB1 FT activation." FT /evidence="ECO:0000269|PubMed:16098514" FT MUTAGEN 56 FT /note="L->A: Partially deficient in guanine nucleotide FT binding. Fully impairs EIF4EBP1 phosphorylation and RPS6KB1 FT activation." FT /evidence="ECO:0000269|PubMed:16098514" FT MUTAGEN 60 FT /note="D->A: Unstable protein, which cannot load GTP." FT /evidence="ECO:0000269|PubMed:22819219" FT MUTAGEN 60 FT /note="D->I: Deficient in guanine nucleotide binding. FT Unable to rescue RPS6KB1 from inactivation by amino-acid FT withdrawal." FT /evidence="ECO:0000269|PubMed:15340059" FT MUTAGEN 60 FT /note="D->K: Unable to bind Mg(2+), preventing FT nucleotide-binding." FT /evidence="ECO:0000269|PubMed:32470140" FT MUTAGEN 64 FT /note="Q->L: Has a higher basal GTPase level, however, is FT still sensitive to TSC2 GAP activity." FT /evidence="ECO:0000269|PubMed:12842888, FT ECO:0000269|PubMed:15340059" FT MUTAGEN 65 FT /note="D->A,E,N: Renders RHEB insensitive to TSC2 FT regulation, leading to impaired regulation of mTORC1 FT signaling." FT /evidence="ECO:0000269|PubMed:22819219" FT MUTAGEN 109 FT /note="K->R: Decreased ubiquitination in response to amino FT acids; when associated with R-135, R-151 and R-178." FT /evidence="ECO:0000269|PubMed:33157014" FT MUTAGEN 135 FT /note="K->R: Decreased ubiquitination in response to amino FT acids; when associated with R-109, R-151 and R-178." FT /evidence="ECO:0000269|PubMed:33157014" FT MUTAGEN 151 FT /note="K->R: Decreased ubiquitination in response to amino FT acids; when associated with R-109, R-135 and R-178." FT /evidence="ECO:0000269|PubMed:33157014" FT MUTAGEN 178 FT /note="K->R: Decreased ubiquitination in response to amino FT acids; when associated with R-109, R-135 and R-151." FT /evidence="ECO:0000269|PubMed:33157014" FT MUTAGEN 181 FT /note="C->S: Reduces the ability to rescue RPS6KB1 from FT inactivation by amino-acid withdrawal." FT /evidence="ECO:0000269|PubMed:12906785, FT ECO:0000269|PubMed:15340059" FT CONFLICT 118 FT /note="G -> W (in Ref. 2; BAA11211)" FT /evidence="ECO:0000305" FT STRAND 5..14 FT /evidence="ECO:0007829|PDB:6BSX" FT HELIX 19..28 FT /evidence="ECO:0007829|PDB:6BSX" FT STRAND 39..49 FT /evidence="ECO:0007829|PDB:6BSX" FT STRAND 52..60 FT /evidence="ECO:0007829|PDB:6BSX" FT STRAND 66..68 FT /evidence="ECO:0007829|PDB:7BTA" FT HELIX 72..75 FT /evidence="ECO:0007829|PDB:6BSX" FT STRAND 80..86 FT /evidence="ECO:0007829|PDB:6BSX" FT HELIX 90..107 FT /evidence="ECO:0007829|PDB:6BSX" FT STRAND 114..119 FT /evidence="ECO:0007829|PDB:6BSX" FT HELIX 124..126 FT /evidence="ECO:0007829|PDB:6BSX" FT HELIX 131..140 FT /evidence="ECO:0007829|PDB:6BSX" FT STRAND 145..147 FT /evidence="ECO:0007829|PDB:6BSX" FT HELIX 153..169 FT /evidence="ECO:0007829|PDB:6BSX" SQ SEQUENCE 184 AA; 20497 MW; 8F4C8080BDF928FD CRC64; MPQSKSRKIA ILGYRSVGKS SLTIQFVEGQ FVDSYDPTIE NTFTKLITVN GQEYHLQLVD TAGQDEYSIF PQTYSIDING YILVYSVTSI KSFEVIKVIH GKLLDMVGKV QIPIMLVGNK KDLHMERVIS YEEGKALAES WNAAFLESSA KENQTAVDVF RRIILEAEKM DGAASQGKSS CSVM //