2. Academic Validation
  3. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex

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

  • Science. 2019 Nov 22;366(6468):971-977. doi: 10.1126/science.aax0364.
Rosalie E Lawrence 1 2,  Simon A Fromm 1,  Yangxue Fu 1,  Adam L Yokom 1,  Do Jin Kim 1,  Ashley M Thelen 1 2,  Lindsey N Young 1,  Chun-Yan Lim 1 2,  Avi J Samelson 2 3,  James H Hurley 4 5 6,  Roberto Zoncu 4 2 5
Affiliations

Affiliations

  • 1 Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
  • 2 The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
  • 3 Institute for Neurodegenerative Diseases, University of California at San Francisco, San Francisco, CA 94158, USA.
  • 4 Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA. jimhurley@berkeley.edu rzoncu@berkeley.edu.
  • 5 California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA.
  • 6 Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
PMID: 31672913 DOI: 10.1126/science.aax0364
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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