Architecture of the human GATOR1 and GATOR1–Rag GTPases complexes

Kuang Shen, Rick K. Huang, Edward J. Brignole, Kendall J. Condon, Max L. Valenstein, Lynne Chantranupong, Aimaiti Bomaliyamu, Abigail Choe, Chuan Hong, Zhiheng Yu () and David M. Sabatini ()
Additional contact information
Kuang Shen: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
Rick K. Huang: Howard Hughes Medical Institute, Janelia Research Campus
Edward J. Brignole: Howard Hughes Medical Institute, Massachusetts Institute of Technology
Kendall J. Condon: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
Max L. Valenstein: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
Lynne Chantranupong: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
Aimaiti Bomaliyamu: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
Abigail Choe: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
Chuan Hong: Howard Hughes Medical Institute, Janelia Research Campus
Zhiheng Yu: Howard Hughes Medical Institute, Janelia Research Campus
David M. Sabatini: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology

Nature, 2018, vol. 556, issue 7699, 64-69

Abstract: Abstract Nutrients, such as amino acids and glucose, signal through the Rag GTPases to activate mTORC1. The GATOR1 protein complex—comprising DEPDC5, NPRL2 and NPRL3—regulates the Rag GTPases as a GTPase-activating protein (GAP) for RAGA; loss of GATOR1 desensitizes mTORC1 signalling to nutrient starvation. GATOR1 components have no sequence homology to other proteins, so the function of GATOR1 at the molecular level is currently unknown. Here we used cryo-electron microscopy to solve structures of GATOR1 and GATOR1–Rag GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 links DEPDC5 and NPRL3, and DEPDC5 contacts the Rag GTPase heterodimer. Biochemical analyses reveal that our GATOR1–Rag GTPases structure is inhibitory, and that at least two binding modes must exist between the Rag GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2–NPRL3 heterodimer and RAGA execute GAP activity. These data reveal the structure of a component of the nutrient-sensing mTORC1 pathway and a non-canonical interaction between a GAP and its substrate GTPase.

Date: 2018
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DOI: 10.1038/nature26158

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