6XJD

Two mouse cGAS catalytic domain binding to human assembled nucleosome

6XJD の概要

• エントリーDOI: 10.2210/pdb6xjd/pdb
• EMDBエントリー: 22046 22206
• 分子名称: Histone H3.2, Histone H4, Histone H2A type 1, ... (8 entities in total)
• 機能のキーワード: immunity, immune system, immune system-dna complex, immune system/dna
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 286790.11

構造登録者

Xu, P.,Li, P.,Zhao, B. (登録日: 2020-06-23, 公開日: 2020-09-16, 最終更新日: 2025-05-28)

主引用文献

Zhao, B.,Xu, P.,Rowlett, C.M.,Jing, T.,Shinde, O.,Lei, Y.,West, A.P.,Liu, W.R.,Li, P.
The molecular basis of tight nuclear tethering and inactivation of cGAS.
Nature, 587:673-677, 2020

PubMed Abstract: Nucleic acids derived from pathogens induce potent innate immune responses. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor that catalyses the synthesis of the cyclic dinucleotide cyclic GMP-AMP, which mediates the induction of type I interferons through the STING-TBK1-IRF3 signalling axis. cGAS was previously thought to not react with self DNA owing to its cytosolic localization; however, recent studies have shown that cGAS is localized mostly in the nucleus and has low activity as a result of tight nuclear tethering. Here we show that cGAS binds to nucleosomes with nanomolar affinity and that nucleosome binding potently inhibits its catalytic activity. To elucidate the molecular basis of cGAS inactivation by nuclear tethering, we determined the structure of mouse cGAS bound to human nucleosome by cryo-electron microscopy. The structure shows that cGAS binds to a negatively charged acidic patch formed by histones H2A and H2B via its second DNA-binding site. High-affinity nucleosome binding blocks double-stranded DNA binding and maintains cGAS in an inactive conformation. Mutations of cGAS that disrupt nucleosome binding alter cGAS-mediated signalling in cells.

PubMed: 32911481
DOI: 10.1038/s41586-020-2749-z

実験手法

ELECTRON MICROSCOPY (6.8 Å)