7CCR

Structure of the 2:2 cGAS-nucleosome complex

7CCR の概要

• エントリーDOI: 10.2210/pdb7ccr/pdb
• EMDBエントリー: 30340
• 分子名称: Histone H3.1, Histone H4, Histone H2A type 1-B/E, ... (7 entities in total)
• 機能のキーワード: cgas, nucleosome, inhibition, cryo-em, immune system, structural protein-transferase-dna complex, structural protein/transferase/dna
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 22
• 化学式量合計: 435878.34

構造登録者

Cao, D.,Han, X.,Fan, X.,Xu, R.M.,Zhang, X. (登録日: 2020-06-17, 公開日: 2020-10-07, 最終更新日: 2025-07-02)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (4.9 Å)