1. Biochemistry and Chemical Biology
  2. Immunology and Inflammation
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The allosteric activation of cGAS underpins its dynamic signaling landscape

  1. Richard M Hooy
  2. Jungsan Sohn  Is a corresponding author
  1. Johns Hopkins University School of Medicine, United States
Research Article
  • Cited 21
  • Views 2,929
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Cite this article as: eLife 2018;7:e39984 doi: 10.7554/eLife.39984

Abstract

Cyclic G/AMP synthase (cGAS) initiates type-1 interferon responses against cytosolic double-stranded (ds)DNA, which range from antiviral gene expression to apoptosis. The mechanism by which cGAS shapes this diverse signaling landscape remains poorly defined. We find that substrate-binding and dsDNA length-dependent binding are coupled to the intrinsic dimerization equilibrium of cGAS, with its N-terminal domain potentiating dimerization. Notably, increasing the dimeric fraction by raising cGAS and substrate concentrations diminishes duplex length-dependent activation, but does not negate the requirement for dsDNA. These results demonstrate that reaction context dictates the duplex length dependence, reconciling competing claims on the role of dsDNA length in cGAS activation. Overall, our study reveals how ligand-mediated allostery positions cGAS in standby, ready to tune its signaling pathway in a switch-like fashion.

Article and author information

Author details

  1. Richard M Hooy

    Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jungsan Sohn

    Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    jsohn@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9570-2544

Funding

American Cancer Society (DMC-RG-15-224)

  • Jungsan Sohn

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Yamuna Krishnan, University of Chicago, United States

Publication history

  1. Received: July 11, 2018
  2. Accepted: October 5, 2018
  3. Accepted Manuscript published: October 8, 2018 (version 1)
  4. Version of Record published: November 1, 2018 (version 2)

Copyright

© 2018, Hooy & Sohn

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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