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

Xu Zhang, Jiaxi Wu, Fenghe Du, Hui Xu, Lijun Sun, Zhe Chen, Chad A Brautigam, Xuewu Zhang, Zhijian Chen

Research output: Contribution to journalArticlepeer-review

147 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)421-430
Number of pages10
JournalCell Reports
Volume6
Issue number3
DOIs
StatePublished - Feb 13 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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