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TitleThe Molecular Basis of Tight Nuclear Tethering and Inactivation of cGAS.
Journal, issue, pagesNature, Year 2020
Publish dateSep 10, 2020
AuthorsBaoyu Zhao / Pengbiao Xu / Chesley M Rowlett / Tao Jing / Omkar Shinde / Yuanjiu Lei / A Phillip West / Wenshe Ray Liu / Pingwei Li /
PubMed AbstractPathogen-derived nucleic acids induce potent innate immune responses. Cyclic GMP-AMP synthase (cGAS) is a dsDNA sensor that catalyzes the synthesis of a cyclic dinucleotide cGAMP, which mediates the ...Pathogen-derived nucleic acids induce potent innate immune responses. Cyclic GMP-AMP synthase (cGAS) is a dsDNA sensor that catalyzes the synthesis of a cyclic dinucleotide cGAMP, which mediates the induction of type I interferons through the STING-TBK1-IRF3 signaling axis. It was widely accepted that cGAS is not reactive to self-DNA due to its cytosolic localization. However, recent studies revealed that cGAS is mostly localized in the nucleus and tight nuclear tethering keeps cGAS inactive. Here we show that cGAS binds to nucleosomes with nanomolar affinity and nucleosome binding potently inhibits the catalytic activity of cGAS. To elucidate the molecular basis of cGAS inactivation by nuclear tethering, we have determined the structure of mouse cGAS bound to human nucleosome by cryo-EM. The structure shows that cGAS binds to a negatively charged acidic patch formed by histone H2A and H2B via its second DNA binding site. High affinity nucleosome binding blocks dsDNA binding and keeps cGAS in an inactive conformation. Mutations of cGAS that disrupt nucleosome binding dramatically affect cGAS mediated signaling in cells.
External linksPubMed:32911481 / Publisher's page
KeywordsDNA BINDING PROTEIN/DNA/TRANSFERASE / Immunity / DNA BINDING PROTEIN-DNA-TRANSFERASE complex / IMMUNE SYSTEM/DNA / IMMUNE SYSTEM / IMMUNE SYSTEM-DNA complex
MethodsEM (single particle)
Resolution2.98 - 6.8 A
Structure data

EMDB-22046:
The mouse cGAS catalytic domain binding to human assembled nucleosome

EMDB-22047:
The mouse cGAS catalytic domain binding to human nucleosome that purified from HEK293T cells

EMDB-22206:
Two mouse cGAS catalytic domain binding to human assembled nucleosome

PDB-6x59:
The mouse cGAS catalytic domain binding to human assembled nucleosome

PDB-6x5a:
The mouse cGAS catalytic domain binding to human nucleosome that purified from HEK293T cells

PDB-6xjd:
Two mouse cGAS catalytic domain binding to human assembled nucleosome

Chemicals

ChemComp-ZN:
ZINC ION / Zinc

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • Human (human)

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