National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM111730
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM130995
United States
National Science Foundation (NSF, United States)
United States
Italian Association for Cancer Research
Italy
Citation
Journal: Sci Adv / Year: 2022 Title: Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation. Authors: Rachel M Jansen / Roberta Peruzzo / Simon A Fromm / Adam L Yokom / Roberto Zoncu / James H Hurley / 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.
Macromolecule #1: Ras-related GTP-binding protein C
Macromolecule
Name: Ras-related GTP-binding protein C / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
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