Structural basis for the dynamic regulation of mTORC1 by amino acids.

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) anchors a conserved signalling pathway that regulates growth in response to nutrient availability^1-5. Amino acids activate mTORC1 through the Rag GTPases, which are regulated by GATOR, a supercomplex consisting of GATOR1, KICSTOR and the nutrient-sensing hub GATOR2 (refs. ^6-9). GATOR2 forms an octagonal cage, with its distinct WD40 domain β-propellers interacting with GATOR1 and the leucine sensors Sestrin1 and Sestrin2 (SESN1 and SESN2) and the arginine sensor CASTOR1 (ref. ¹⁰). The mechanisms through which these sensors regulate GATOR2 and how they detach from it upon binding their cognate amino acids remain unknown. Here, using cryo-electron microscopy, we determined the structures of a stabilized GATOR2 bound to either Sestrin2 or CASTOR1. The sensors occupy distinct and non-overlapping binding sites, disruption of which selectively impairs the ability of mTORC1 to sense individual amino acids. We also resolved the apo (leucine-free) structure of Sestrin2 and characterized the amino acid-induced structural rearrangements within Sestrin2 and CASTOR1 that trigger their dissociation from GATOR2. Binding of either sensor restricts the dynamic WDR24 β-propeller of GATOR2, a domain essential for nutrient-dependent mTORC1 activation. These findings reveal the allosteric mechanisms that convey amino acid sufficiency to GATOR2 and the ensuing structural changes that lead to mTORC1 activation.