4.4 Å Resolution Cryo-EM structure of human mTOR Complex 1

Protein and Cell

Volumn 7, Issue 12, 2016, Pages 878-887

  Yang, Huirong ^a,b,c   Wang, Jia ^d   Liu, Mengjie ^a,b,c   Chen, Xizi ^a,b,c   Huang, Min ^e   Tan, Dan ^f   Dong, Meng Qiu ^f   Wong, Catherine C L ^e   Wang, Jiawei ^d   Xu, Yanhui ^a,b,c   Wang, Hong Wei ^d  

^a FUDAN UNIVERSITY SHANGHAI CANCER CENTER   (China)

^b FUDAN UNIVERSITY   (China)

^c FUDAN UNIVERSITY   (China)

^d Tsinghua University   (China)

^e INSTITUTE OF BIOCHEMISTRY AND CELL BIOLOGY   (China)

^f NATIONAL INSTITUTE OF BIOLOGICAL SCIENCES   (China)

Author keywords

cryo electron microscopy; mTORC1; structure

Indexed keywords

GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PEPTIDYLPROLYL ISOMERASE; MULTIPROTEIN COMPLEX; TARGET OF RAPAMYCIN KINASE;

ARTICLE; CASPASE ASSAY; CELL CULTURE; CONTROLLED STUDY; CROSS LINKING; CRYOELECTRON MICROSCOPY; ENZYME ACTIVITY; GENE EXPRESSION REGULATION; GENETIC TRANSFECTION; HUMAN; HUMAN CELL; IMAGE PROCESSING; IMMUNOBLOTTING; KINASE ASSAY; MASS SPECTROMETRY; POLYACRYLAMIDE GEL ELECTROPHORESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN PURIFICATION; PROTEIN STRUCTURE; RAPTOR; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; CELL LINE; CHEMISTRY; PROCEDURES; PROTEIN QUATERNARY STRUCTURE; ULTRASTRUCTURE;

CELL LINE; CRYOELECTRON MICROSCOPY; HUMANS; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MULTIPROTEIN COMPLEXES; PROTEIN STRUCTURE, QUATERNARY; TOR SERINE-THREONINE KINASES;

EID: 85000879059     PISSN: 1674800X     EISSN: 16748018     Source Type: Journal    
DOI: 10.1007/s13238-016-0346-6     Document Type: Article

References (37)

1. Adams PD, Afonine PV, Bunkóczi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung L-W, Kapral GJ, Grosse-Kunstleve RW (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D 66:213–221
2. Aylett CH, Sauer E, Imseng S, Boehringer D, Hall MN, Ban N, Maier T (2016) Architecture of human mTOR complex 1. Science 351:48–52
3. Baretic D, Berndt A, Ohashi Y, Johnson CM, Williams RL (2016) Tor forms a dimer through an N-terminal helical solenoid with a complex topology. Nat Commun 7:11016
4. Benjamin D, Colombi M, Moroni C, Hall MN (2011) Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 10:868–880
5. Chen SX, McMullan G, Faruqi AR, Murshudov GN, Short JM, Scheres SHW, Henderson R (2013) High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy. Ultramicroscopy 135:24–35
6. Choi J, Chen J, Schreiber SL, Clardy J (1996) Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science (NY) 273:239–242
7. Dazert E, Hall MN (2011) mTOR signaling in disease. Curr Opin Cell Biol 23:744–755
8. Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, Tee AR (2014) ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 7:737–747
9. Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, Oliner JD, McKeon F, Haber DA (2002) REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell 10:995–1005
10. Emsley P, Lohkamp B, Scott W, Cowtan K (2010) Features and development of COOT. Acta Crystallogr D 66:486–501
11. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 11:1457–1466
12. Ginalski K, Zhang H, Grishin NV (2004) Raptor protein contains a caspase-like domain. Trends Biochem Sci 29:522–524
13. Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N (1999) Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 13:1422–1437
14. Holz MK, Blenis J (2005) Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J Biol Chem 280:26089–26093
15. Holz MK, Ballif BA, Gygi SP, Blenis J (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123:569–580
16. Inoki K, Li Y, Xu T, Guan KL (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829–1834
17. Inoki K, Corradetti MN, Guan KL (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37:19–24
18. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175
19. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10:935–945
20. Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr 26:283–291
21. Li X, Mooney P, Zheng S, Booth CR, Braunfeld MB, Gubbens S, Agard DA, Cheng Y (2013) Electron counting and beam-induced motion correction enable near-atomic-resolution single-particle cryo-EM. Nat Methods 10:584–590
22. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10:457–468
23. Mindell JA, Grigorieff N (2003) Accurate determination of local defocus and specimen tilt in electron microscopy. J Struct Biol 142:334–347
24. Rossmann MG, Bernal R, Pletnev SV (2001) Combining electron microscopic with X-ray crystallographic structures. J Struct Biol 136:190–200
25. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302
26. Scheres SH (2012) RELION: implementation of a Bayesian approach to cryo-EM structure determination. J Struct Biol 180:519–530
27. Stretton C, Hoffmann TM, Munson MJ, Prescott A, Taylor PM, Ganley IG, Hundal HS (2015) GSK3-mediated raptor phosphorylation supports amino-acid-dependent mTORC1-directed signalling. Biochem J 470:207–221
28. Tee AR, Blenis J (2005) mTOR, translational control and human disease. Semin Cell Dev Biol 16:29–37
29. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13:1259–1268
30. Vriend G (1990) WHAT IF: a molecular modeling and drug design program. J Mol Graph 8:52–56
31. Wang QS, Yu F, Huang S, Sun B, Zhang KH, Liu K, Wang ZJ, Xu CY, Wang SS, Yang LF et al (2015) The macromolecular crystallography beamline of SSRF. Nucl Sci Technol 26:12–17
32. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484
33. Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu JW, Strack S, Jeffrey PD, Shi Y (2006) Structure of the protein phosphatase 2A holoenzyme. Cell 127:1239–1251
34. Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP (2013) mTOR kinase structure, mechanism and regulation. Nature 497:217–223
35. Yip CK, Murata K, Walz T, Sabatini DM, Kang SA (2010) Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell 38:768–774
36. Yuan HX, Wang Z, Yu FX, Li F, Russell RC, Jewell JL, Guan KL (2015) NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition. Genes Dev 29:2362–2376
37. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35