The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop

  • Cell Rep. 2014 Feb 13;6(3):421-30. doi: 10.1016/j.celrep.2014.01.003.
Xu Zhang  1 ,  Jiaxi Wu  2 ,  Fenghe Du  3 ,  Hui Xu  2 ,  Lijun Sun  3 ,  Zhe Chen  4 ,  Chad A Brautigam  4 ,  Xuewu Zhang  5 ,  Zhijian J Chen  6
Affiliations
  • 1. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Electronic address: [email protected].
  • 2. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
  • 3. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
  • 4. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
  • 5. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
  • 6. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Electronic address: [email protected].
PMID: 24462292 DOI: 10.1016/j.celrep.2014.01.003
Abstract

The presence of DNA in the cytoplasm is a danger signal that triggers immune and inflammatory responses. Cytosolic DNA binds to and activates cyclic GMP-AMP (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP binds to the adaptor protein STING and activates a signaling cascade that leads to the production of type I interferons and Other cytokines. Here, we report the crystal structures of human cGAS in its apo form, representing its autoinhibited conformation as well as in its cGAMP- and sulfate-bound forms. These structures reveal switch-like conformational changes of an activation loop that result in the rearrangement of the catalytic site. The structure of DNA-bound cGAS reveals a complex composed of dimeric cGAS bound to two molecules of DNA. Functional analyses of cGAS mutants demonstrate that both the protein-protein interface and the two DNA binding surfaces are critical for cGAS activation. These results provide insights into the mechanism of DNA sensing by cGAS.