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TitleStructural basis of nucleosome-dependent cGAS inhibition.
Journal, issue, pagesScience, Vol. 370, Issue 6515, Page 450-454, Year 2020
Publish dateOct 23, 2020
AuthorsJoshua A Boyer / Cathy J Spangler / Joshua D Strauss / Andrew P Cesmat / Pengda Liu / Robert K McGinty / Qi Zhang /
PubMed AbstractCyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) recognizes cytosolic foreign or damaged DNA to activate the innate immune response to infection, inflammatory ...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.
External linksScience / PubMed:32913000 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 3.9 Å
Structure data

22408

7jo9

EMDB-22408, PDB-7jo9:
1:1 cGAS-nucleosome complex
Method: EM (single particle) / Resolution: 3.3 Å

22409

7joa

EMDB-22409, PDB-7joa:
2:1 cGAS-nucleosome complex
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-22413:
1:1 cGAS(mask)-NCP map
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • synthetic construct (others)
KeywordsDNA Binding Protein/DNA/Transferase / cGAS / nucleosome / cyclic GMP-AMP synthase / DNA Binding Protein-DNA-Transferase complex

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