Research Article

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

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Science  22 Nov 2019:
Vol. 366, Issue 6468, pp. 971-977
DOI: 10.1126/science.aax0364

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Cellular response to nutrient status

An intricate regulatory mechanism is taking shape around control of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase complex. Physiological responses of cells to nutrient abundance is regulated by signaling through mTORC1, which interacts with a complex of other proteins at the lysosome that includes small guanosine triphosphatases (GTPases), GTPase-activating proteins, and others. Lawrence et al. present a cryo–electron microscopy structure and biochemical experiments that reveal that the small GTPases act in unanticipated ways in the complex. The tumor suppressor folliculin (FLCN), along with FLCN-interacting protein 2, interacts with its partner GTPase RagC in both active and inactive states, suggesting that a particularly elaborate and stringent regulatory mechanism is at work.

Science, this issue p. 971

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 human lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), and the RagAGDP:RagCGTP GTPases as they exist in the starved state with their lysosomal anchor Ragulator complex and determined its cryo–electron microscopy structure to 3.6 angstroms. The RagC-GAP activity of FLCN was inhibited within the LFC, owing 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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