Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex.

ABSTRACT: The transcription factor TFEB is a master regulator of lysosomal biogenesis and autophagy¹. The phosphorylation of TFEB by the mechanistic target of rapamycin complex 1 (mTORC1)^2-5 is unique in its mTORC1 substrate recruitment mechanism, which is strictly dependent on the amino acid-mediated activation of the RagC GTPase activating protein FLCN^6,7. TFEB lacks the TOR signalling motif responsible for the recruitment of other mTORC1 substrates. We used cryogenic-electron microscopy to determine the structure of TFEB as presented to mTORC1 for phosphorylation, which we refer to as the 'megacomplex'. Two full Rag-Ragulator complexes present each molecule of TFEB to the mTOR active site. One Rag-Ragulator complex is bound to Raptor in the canonical mode seen pre

SUBMITTER: Cui Z 

PROVIDER: S-EPMC9931586 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature