7UXH
cryo-EM structure of the mTORC1-TFEB-Rag-Ragulator complex
This is a non-PDB format compatible entry.
Summary for 7UXH
| Entry DOI | 10.2210/pdb7uxh/pdb |
| Related | 7UXC |
| EMDB information | 26852 26857 26861 |
| Descriptor | Serine/threonine-protein kinase mTOR, Ragulator complex protein LAMTOR5, Transcription factor EB, ... (15 entities in total) |
| Functional Keywords | mtorc1, tfeb, lysosome biogenesis, autophagy, signaling protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 36 |
| Total formula weight | 1644644.58 |
| Authors | Cui, Z.,Hurley, J. (deposition date: 2022-05-05, release date: 2022-11-30, Last modification date: 2024-06-12) |
| Primary citation | 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 Cited by 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: 36697823DOI: 10.1038/s41586-022-05652-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.2 Å) |
Structure validation
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