Research Article

Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex

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Science  31 Oct 2019:
eaax0364
DOI: 10.1126/science.aax0364

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Abstract

The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) Activating Protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. To determine the lysosomal function of FLCN, we reconstituted the lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), the RagAGDP:RagCGTP GTPases as they exist in the starved state with their lysosomal anchor Ragulator complex, and determined its cryo-EM structure to 3.6 Å. The RagC-GAP activity of FLCN was inhibited within LFC, due to displacement of a catalytically required Arginine in FLCN from the RagC nucleotide. Disassembly of the LFC and release of the RagC-GAP activity of FLCN enabled mTORC1-dependent regulation of the master regulator of lysosomal biogenesis, transcription factor E3, implicating the LFC as a checkpoint in mTORC1 signaling.

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