Format

Send to

Choose Destination
Immunity. 2013 Dec 12;39(6):1019-31. doi: 10.1016/j.immuni.2013.10.019.

Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization.

Author information

1
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA.
2
Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA.
3
Department of Molecular Genetics, Biochemistry & Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
4
X-Ray Science Division, Advanced Photon Source, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439, USA.
5
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128, USA. Electronic address: pingwei@tamu.edu.

Abstract

Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor mediating innate antimicrobial immunity. It catalyzes the synthesis of a noncanonical cyclic dinucleotide, 2',5' cGAMP, that binds to STING and mediates the activation of TBK1 and IRF-3. Activated IRF-3 translocates to the nucleus and initiates the transcription of the IFN-β gene. The structure of mouse cGAS bound to an 18 bp dsDNA revealed that cGAS interacts with dsDNA through two binding sites, forming a 2:2 complex. Enzyme assays and IFN-β reporter assays of cGAS mutants demonstrated that interactions at both DNA binding sites are essential for cGAS activation. Mutagenesis and DNA binding studies showed that the two sites bind dsDNA cooperatively and that site B plays a critical role in DNA binding. The structure of mouse cGAS bound to dsDNA and 2',5' cGAMP provided insight into the catalytic mechanism of cGAS. These results demonstrated that cGAS is activated by dsDNA-induced oligomerization.

PMID:
24332030
PMCID:
PMC3886715
DOI:
10.1016/j.immuni.2013.10.019
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center