7CCQ

Structure of the 1:1 cGAS-nucleosome complex

Summary for 7CCQ

• Entry DOI: 10.2210/pdb7ccq/pdb
• EMDB information: 30339
• Descriptor: Histone H3.1, Histone H4, Histone H2A type 1-B/E, ... (7 entities in total)
• Functional Keywords: cgas, nucleosome, inhibition, cryo-em, immune system, structural protein-transferase-dna complex, structural protein/transferase/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 11
• Total formula weight: 217939.17

Authors

Cao, D.,Han, X.,Fan, X.,Xu, R.M.,Zhang, X. (deposition date: 2020-06-17, release date: 2020-10-07, Last modification date: 2024-03-27)

Primary citation

Cao, D.,Han, X.,Fan, X.,Xu, R.M.,Zhang, X.
Structural basis for nucleosome-mediated inhibition of cGAS activity.
Cell Res., 30:1088-1097, 2020

PubMed Abstract: Activation of cyclic GMP-AMP synthase (cGAS) through sensing cytosolic double stranded DNA (dsDNA) plays a pivotal role in innate immunity against exogenous infection as well as cellular regulation under stress. Aberrant activation of cGAS induced by self-DNA is related to autoimmune diseases. cGAS accumulates at chromosomes during mitosis or spontaneously in the nucleus. Binding of cGAS to the nucleosome competitively attenuates the dsDNA-mediated cGAS activation, but the molecular mechanism of the attenuation is still poorly understood. Here, we report two cryo-electron microscopy structures of cGAS-nucleosome complexes. The structures reveal that cGAS interacts with the nucleosome as a monomer, forming 1:1 and 2:2 complexes, respectively. cGAS contacts the nucleosomal acidic patch formed by the H2A-H2B heterodimer through the dsDNA-binding site B in both complexes, and could interact with the DNA from the other symmetrically placed nucleosome via the dsDNA-binding site C in the 2:2 complex. The bound nucleosome inhibits the activation of cGAS through blocking the interaction of cGAS with ligand dsDNA and disrupting cGAS dimerization. R236A or R255A mutation of cGAS impairs the binding between cGAS and the nucleosome, and largely relieves the nucleosome-mediated inhibition of cGAS activity. Our study provides structural insights into the inhibition of cGAS activity by the nucleosome, and advances the understanding of the mechanism by which hosts avoid the autoimmune attack caused by cGAS.

PubMed: 33051594
DOI: 10.1038/s41422-020-00422-4

Experimental method

ELECTRON MICROSCOPY (3.8 Å)