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Architecture of the human GATOR1 and GATOR1–Rag GTPases complexes

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  • Kuang Shen

    (Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    Koch Institute for Integrative Cancer Research
    Broad Institute of Harvard 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
    Massachusetts Institute of Technology)

  • Kendall J. Condon

    (Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    Koch Institute for Integrative Cancer Research
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Max L. Valenstein

    (Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    Koch Institute for Integrative Cancer Research
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Lynne Chantranupong

    (Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    Koch Institute for Integrative Cancer Research
    Broad Institute of Harvard 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
    Howard Hughes Medical Institute, Massachusetts Institute of Technology
    Koch Institute for Integrative Cancer Research
    Broad Institute of Harvard and Massachusetts Institute of Technology)

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.

Suggested Citation

  • Kuang Shen & Rick K. Huang & Edward J. Brignole & Kendall J. Condon & Max L. Valenstein & Lynne Chantranupong & Aimaiti Bomaliyamu & Abigail Choe & Chuan Hong & Zhiheng Yu & David M. Sabatini, 2018. "Architecture of the human GATOR1 and GATOR1–Rag GTPases complexes," Nature, Nature, vol. 556(7699), pages 64-69, April.
  • Handle: RePEc:nat:nature:v:556:y:2018:i:7699:d:10.1038_nature26158
    DOI: 10.1038/nature26158
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    Cited by:

    1. Weize Wang & Ling Liang & Zonglin Dai & Peng Zuo & Shang Yu & Yishuo Lu & Dian Ding & Hongyi Chen & Hui Shan & Yan Jin & Youdong Mao & Yuxin Yin, 2024. "A conserved N-terminal motif of CUL3 contributes to assembly and E3 ligase activity of CRL3KLHL22," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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