RHEB promotes allosteric activation of mTOR whereas PRAS40 blocks substrate recruitment sites.
Major finding: RHEB promotes allosteric activation of mTOR whereas PRAS40 blocks substrate recruitment sites.
Clinical relevance: Cancer-associated mTORC1 hyperactivating mutations mimic RHEB to relieve mTOR autoinhibition.
Impact: mTORC1 structures reveal mechanisms of regulation that can be disrupted by cancer-associated mutations.
The mTORC1 complex, comprised of mTOR and the subunits RAPTOR and mLST8, is commonly mutated in cancer and controls many aspects of cell growth and metabolism by sensing levels of nutrients and growth factors. mTORC1 is activated by the small GTPase RAS homolog MTORC1 binding (RHEB) at the lysosomal membrane and can be inhibited by AKT1 substrate 1 (PRAS40, encoded by AKT1S1). The overall structure of mTORC1 has been described from 5.9 Å and 4.4 Å cryo-electron microscopy (cryo-EM) reconstructions, but the biochemical and structural mechanisms by which RHEB and PRAS40 regulate mTORC1 activity are not well understood, prompting Yang and colleagues to obtain higher-resolution cryo-EM or crystal structures of several mTORC1 complexes. RAPTOR binds to a TOR signaling sequence (TOS) motif in substrates including the S6K1 substrate, which had previously been suggested to be recruited by the mTOR FRB domain. Determination of the 1.75 Å FRB-S6K1 crystal structure confirmed that the FRB domain is a substrate recruitment site. The RAPTOR–PRAS40 (3.35 Å) structure revealed that PRAS40 blocked the mTOR FKBP12–rapamycin-binding (FRB) substrate–recruitment site as well as RAPTOR binding to the TOS motif. The mTORC1 (3.0 Å) and RHEB–mTORC1 (3.4 Å) structures showed that RHEB bound mTOR away from the active kinase site and caused a global conformational change (including conformation changes within the FAT domain) that realigned the active site residues for an allosteric catalytic acceleration, providing a structural mechanism by which RHEB activates mTORC1. Hyperactivating mTOR mutations in cancer predominantly occur in or near the FAT domain, and these mutations reduced barriers to adoption of the active conformation, thereby mimicking the effects of RHEB and relieving autoinhibition. Taken together, these findings elucidate structural mechanisms by which mTORC1 selects substrates and is activated by cancer-associated mutations.
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