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Structure paper

TitleMechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.
Journal, issue, pagesNature, Vol. 552, Issue 7685, Page 368-373, Year 2017
Publish dateDec 21, 2017
AuthorsHaijuan Yang / Xiaolu Jiang / Buren Li / Hyo J Yang / Meredith Miller / Angela Yang / Ankita Dhar / Nikola P Pavletich /
PubMed AbstractThe mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the ...The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.
External linksNature / PubMed:29236692 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.75 - 3.8 Å
Structure data

7086

6bcu

EMDB-7086: active dimer
PDB-6bcu: Cryo-EM structure of the activated RHEB-mTORC1 refined to 3.4 angstrom
Method: EM (single particle) / Resolution: 3.8 Å

7087

6bcx

EMDB-7087, PDB-6bcx:
mTORC1 structure refined to 3.0 angstroms
Method: EM (single particle) / Resolution: 3.23 Å

PDB-5wbh:
Structure of the FRB domain of mTOR bound to a substrate recruitment peptide of S6K1
Method: X-RAY DIFFRACTION / Resolution: 1.75 Å

PDB-5wbi:
Crystal structure of the Arabidopsis thaliana Raptor
Method: X-RAY DIFFRACTION / Resolution: 3 Å

PDB-5wbj:
Crystal structure of the arabidopsis thaliana Raptor in complex with the TOS peptide of human 4EBP1
Method: X-RAY DIFFRACTION / Resolution: 3 Å

PDB-5wbk:
Crystal structure of the arabidopsis thaliana Raptor in complex with the TOS peptide of human S6K1
Method: X-RAY DIFFRACTION / Resolution: 3.11 Å

PDB-5wbl:
Crystal structure of the Arabidopsis thaliana Raptor in complex with the TOS peptide of human PRAS40
Method: X-RAY DIFFRACTION / Resolution: 3.35 Å

PDB-5wbu:
Crystal structure of mTOR(deltaN)-mLST8-PRAS40(alpha-helix & beta-strand) complex
Method: X-RAY DIFFRACTION / Resolution: 3.42 Å

PDB-5wby:
Crystal structure of mTOR(deltaN)-mLST8-PRAS40(beta-strand) complex
Method: X-RAY DIFFRACTION / Resolution: 3.1 Å

Chemicals

ChemComp-HOH:
WATER

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
  • arabidopsis thaliana (thale cress)
KeywordsTRANSFERASE / PROTEIN BINDING / FRB / Raptor / TOS / complex / WD40 / PRAS40 / PRAS40 beta / PIKK

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