2. Academic Validation
  3. Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9

Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9

  • Nat Struct Mol Biol. 2020 Nov;27(11):1017-1023. doi: 10.1038/s41594-020-0490-9.
Simon A Fromm 1 2,  Rosalie E Lawrence 1 2 3,  James H Hurley 4 5 6
Affiliations

Affiliations

  • 1 Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
  • 2 California Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA.
  • 3 Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • 4 Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA. [email protected].
  • 5 California Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA. [email protected].
  • 6 Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. [email protected].
PMID: 32868926 DOI: 10.1038/s41594-020-0490-9
Abstract

The Rag GTPases (Rags) recruit mTORC1 to the lysosomal membrane in response to nutrients, where it is then activated in response to energy and growth factor availability. The lysosomal folliculin (FLCN) complex (LFC) consists of the inactive Rag dimer, the pentameric scaffold Ragulator, and the FLCN:FNIP2 (FLCN-interacting protein 2) GTPase activating protein (GAP) complex, and prevents Rag dimer activation during amino acid starvation. How the LFC is disassembled upon amino acid refeeding is an outstanding question. Here we show that the cytoplasmic tail of the human lysosomal solute carrier family 38 member 9 (SLC38A9) destabilizes the LFC and thereby triggers GAP activity of FLCN:FNIP2 toward RagC. We present the cryo-EM structures of Rags in complex with their lysosomal anchor complex Ragulator and the cytoplasmic tail of SLC38A9 in the pre- and post-GTP hydrolysis state of RagC, which explain how SLC38A9 destabilizes the LFC and so promotes Rag dimer activation.

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