7UXC

cryo-EM structure of the mTORC1-TFEB-Rag-Ragulator complex with symmetry expansion

7UXC の概要

• エントリーDOI: 10.2210/pdb7uxc/pdb
• EMDBエントリー: 26852 26857
• 分子名称: Serine/threonine-protein kinase mTOR, Ragulator complex protein LAMTOR5, Transcription factor EB, ... (15 entities in total)
• 機能のキーワード: mtorc1, tfeb, lysosome biogenesis, autophagy, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 18
• 化学式量合計: 822322.29

構造登録者

Cui, Z.,Hurley, J. (登録日: 2022-05-05, 公開日: 2022-11-30, 最終更新日: 2024-06-12)

主引用文献

Cui, Z.,Napolitano, G.,de Araujo, M.E.G.,Esposito, A.,Monfregola, J.,Huber, L.A.,Ballabio, A.,Hurley, J.H.
Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex.
Nature, 614:572-579, 2023

PubMed Abstract: The transcription factor TFEB is a master regulator of lysosomal biogenesis and autophagy. The phosphorylation of TFEB by the mechanistic target of rapamycin complex 1 (mTORC1) 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. 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 previously in the absence of TFEB. A second Rag-Ragulator complex (non-canonical) docks onto the first through a RagC GDP-dependent contact with the second Ragulator complex. The non-canonical Rag dimer binds the first helix of TFEB with a RagC-dependent aspartate clamp in the cleft between the Rag G domains. In cellulo mutation of the clamp drives TFEB constitutively into the nucleus while having no effect on mTORC1 localization. The remainder of the 108-amino acid TFEB docking domain winds around Raptor and then back to RagA. The double use of RagC GDP contacts in both Rag dimers explains the strong dependence of TFEB phosphorylation on FLCN and the RagC GDP state.

PubMed: 36697823
DOI: 10.1038/s41586-022-05652-7

実験手法

ELECTRON MICROSCOPY (3.2 Å)