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TitleStructural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation.
Journal, issue, pagesSci Adv, Vol. 8, Issue 37, Page eadd2926, Year 2022
Publish dateSep 16, 2022
AuthorsRachel M Jansen / Roberta Peruzzo / Simon A Fromm / Adam L Yokom / Roberto Zoncu / James H Hurley /
PubMed AbstractThe 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 linksSci Adv / PubMed:36103527 / PubMed Central
MethodsEM (single particle)
Resolution3.53 Å
Structure data

EMDB-27435, PDB-8dhb:
Active FLCN GAP complex
Method: EM (single particle) / Resolution: 3.53 Å

Chemicals

ChemComp-CZC:
[(2~{R},3~{S},4~{R},5~{R})-5-[2,6-bis(oxidanylidene)-3~{H}-purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl phosphono hydrogen phosphate

ChemComp-BEF:
BERYLLIUM TRIFLUORIDE ION

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / FLCN / Rag-Ragulator / GTPase Activating Protein / mTORC1 signaling

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