Structure of the lysosomal mTORC1–TFEB–Rag–Ragulator megacomplex

Cui, Zhicheng; Napolitano, Gennaro; Araújo, Mariana E. G. de; Esposito, Alessandra; Monfregola, Jlenia; Huber, Lukas A.; Ballabio, Andrea; Hurley, James H.

doi:10.1038/s41586-022-05652-7

articleNatureJan 25, 2023HYBRID OA

Structure of the lysosomal mTORC1–TFEB–Rag–Ragulator megacomplex

ZCZhicheng Cui GNGennaro Napolitano MEMariana E. G. de Araújo AEAlessandra Esposito JMJlenia Monfregola

QB3 · University of California, Berkeley · +6 more institutions

PubMed

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Abstract

Abstract The transcription factor TFEB is a master regulator of lysosomal biogenesis and autophagy 1 . 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…

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Topics & keywords

Topics

Keywords

TFEB
Folliculin
Basic helix-loop-helix leucine zipper transcription factors
mTORC1
Cell biology
Mechanistic target of rapamycin
Phosphorylation
Biology

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