6W10

Structure of mouse TREX1 with E198K disease-associated mutation

6W10 の概要

• エントリーDOI: 10.2210/pdb6w10/pdb
• 分子名称: Three-prime repair exonuclease 1 (2 entities in total)
• 機能のキーワード: nuclease, dnase, innate immunity, autoimmunity, hydrolase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 52822.21

構造登録者

Zhou, W.,Mohr, L.,Maciejowski, J.,Kranzusch, P.J. (登録日: 2020-03-03, 公開日: 2021-02-17, 最終更新日: 2023-10-18)

主引用文献

Zhou, W.,Mohr, L.,Maciejowski, J.,Kranzusch, P.J.
cGAS phase separation inhibits TREX1-mediated DNA degradation and enhances cytosolic DNA sensing.
Mol.Cell, 81:739-755.e7, 2021

PubMed Abstract: Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for the immune response to cancer and pathogen infection. Here, we discover that cGAS-DNA phase separation is required to resist negative regulation and allow efficient sensing of immunostimulatory DNA. We map the molecular determinants of cGAS condensate formation and demonstrate that phase separation functions to limit activity of the cytosolic exonuclease TREX1. Mechanistically, phase separation forms a selective environment that suppresses TREX1 catalytic function and restricts DNA degradation to an outer shell at the droplet periphery. We identify a TREX1 mutation associated with the severe autoimmune disease Aicardi-Goutières syndrome that increases penetration of TREX1 into the repressive droplet interior and specifically impairs degradation of phase-separated DNA. Our results define a critical function of cGAS-DNA phase separation and reveal a molecular mechanism that balances cytosolic DNA degradation and innate immune activation.

PubMed: 33606975
DOI: 10.1016/j.molcel.2021.01.024

実験手法

X-RAY DIFFRACTION (1.80003386368 Å)