6W10

Structure of mouse TREX1 with E198K disease-associated mutation

Summary for 6W10

• Entry DOI: 10.2210/pdb6w10/pdb
• Descriptor: Three-prime repair exonuclease 1 (2 entities in total)
• Functional Keywords: nuclease, dnase, innate immunity, autoimmunity, hydrolase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 52822.21

Authors

Zhou, W.,Mohr, L.,Maciejowski, J.,Kranzusch, P.J. (deposition date: 2020-03-03, release date: 2021-02-17, Last modification date: 2023-10-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.80003386368 Å)