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-Structure paper
Title | Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation. |
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Journal, issue, pages | Sci Adv, Vol. 8, Issue 37, Page eadd2926, Year 2022 |
Publish date | Sep 16, 2022 |
Authors | Rachel M Jansen / Roberta Peruzzo / Simon A Fromm / Adam L Yokom / Roberto Zoncu / James H Hurley / |
PubMed Abstract | The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) ...The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) is a RagC/D guanosine triphosphatase (GTPase)-activating protein (GAP) that regulates mTORC1 phosphorylation of MiT-TFE transcription factors, controlling lysosome biogenesis and autophagy. We determined the cryo-electron microscopy structure of the active FLCN complex (AFC) containing FLCN, FNIP2, the N-terminal tail of SLC38A9, the RagA:RagC GTPase dimer, and the Ragulator scaffold. Relative to the inactive lysosomal FLCN complex structure, FLCN reorients by 90°, breaks contact with RagA, and makes previously unseen contacts with RagC that position its Arg finger for catalysis. Disruption of the AFC-specific interfaces of FLCN and FNIP2 with RagC eliminated GAP activity and led to nuclear retention of TFE3, with no effect on mTORC1 substrates S6K or 4E-BP1. The structure provides a basis for regulation of an mTORC1 substrate-specific pathway and a roadmap to discover MiT-TFE family selective mTORC1 antagonists. |
External links | Sci Adv / PubMed:36103527 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.53 Å |
Structure data | EMDB-27435, PDB-8dhb: |
Chemicals | ChemComp-CZC: ChemComp-BEF: ChemComp-GDP: |
Source |
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Keywords | SIGNALING PROTEIN / FLCN / Rag-Ragulator / GTPase Activating Protein / mTORC1 signaling |