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

Zhang X, Wu J, Du F, Xu H, Sun L, Chen Z, Brautigam CA, Zhang X, Chen ZJ
Cell Rep 6 421-30 (2014)
Related entries: 4o68, 4o69, 4o6a

Cited: 243 times
EuropePMC logo PMID: 24462292

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.

Articles - 4o67 mentioned but not cited (6)

  1. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Zhang X, Wu J, Du F, Xu H, Sun L, Chen Z, Brautigam CA, Zhang X, Chen ZJ. Cell Rep 6 421-430 (2014)
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