Journal
SCIENCE
Volume 370, Issue 6515, Pages 450-454Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abd0609
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Funding
- University of North Carolina at Chapel Hill
- NIH [1R35GM133498, R21CA234979, F99CA253730]
- Searle Scholars award
- Pew-Stewart Scholars award
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Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) recognizes cytosolic foreign or damaged DNA to activate the innate immune response to infection, inflammatory diseases, and cancer. By contrast, cGAS reactivity against self-DNA in the nucleus is suppressed by chromatin tethering. We report a 3.3-angstrom-resolution cryo-electron microscopy structure of cGAS in complex with the nucleosome core particle. The structure reveals that cGAS uses two conserved arginines to anchor to the nucleosome acidic patch. The nucleosome-binding interface exclusively occupies the strong double-stranded DNA (dsDNA)-binding surface on cGAS and sterically prevents cGAS from oligomerizing into the functionally active 2:2 cGAS-dsDNA state. These findings provide a structural basis for how cGAS maintains an inhibited state in the nucleus and further exemplify the role of the nucleosome in regulating diverse nuclear protein functions.
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