@article{95a606f3a95c4efaafda3c56963ade9c,
title = "Structure of Human cGAS Reveals a Conserved Family of Second-Messenger Enzymes in Innate Immunity",
abstract = "Innate immune recognition of foreign nucleic acids induces protective interferon responses. Detection of cytosolic DNA triggers downstream immune signaling through activation of cyclic GMP-AMP synthase (cGAS). We report here the crystal structure of human cGAS, revealing an unanticipated zinc-ribbon DNA-binding domain appended to a core enzymatic nucleotidyltransferase scaffold. The catalytic core of cGAS is structurally homologous to the RNA-sensing enzyme, 2'-5' oligo-adenylate synthase (OAS), and divergent C-terminal domains account for specific ligand-activation requirements of each enzyme. We show that the cGAS zinc ribbon is essential for STING-dependent induction of the interferon response and that conserved amino acids displayed within the intervening loops are required for efficient cytosolic DNA recognition. These results demonstrate that cGAS and OAS define a family of innate immunity sensors and that structural divergence from a core nucleotidyltransferase enables second-messenger responses to distinct foreign nucleic acids.",
author = "Kranzusch, {Philip J.} and Lee, {Amy Si Ying} and Berger, {James M.} and Doudna, {Jennifer A.}",
note = "Funding Information: Experiments were designed by P.J.K. in consultation with J.M.B. and J.A.D., structural and biochemical work was performed by P.J.K., and cell-signaling assays were performed by A.S.Y.L. The manuscript was written by P.J.K. and J.A.D., and all authors contributed to editing the manuscript and support the conclusions. The authors are grateful to the staff at Beamlines 11.1 and 12.2 of the Stanford Synchrotron Radiation Lightsource (SSRL) and Beamline 8.3.1 of the Lawrence Berkeley National Lab Advanced Light Source for their technical assistance; T. Doukov (Stanford, SSRL) for assistance with data collection and analysis; M. Jinek (University of Zurich), A. Lyubimov, and J. Cate (University of California, Berkeley) for advice on phase determination and model building; D. King (HHMI, University of California, Berkeley) for mass spectrometry; J. Schoggins and C. Rice (Rockefeller University) for reagents; M. Solovykh for technical assistance; and Y. Bai, S. Floor, and members of the Doudna and Berger labs for helpful comments and discussion. This work was funded by HHMI (J.A.D.), the G. Harold and Leila Y. Mathers Foundation (J.M.B.), and the NIGMS Center for RNA Systems Biology (P.J.K., A.S.Y.L., and J.A.D.). J.A.D. is an HHMI Investigator. ",
year = "2013",
month = may,
day = "30",
doi = "10.1016/j.celrep.2013.05.008",
language = "English (US)",
volume = "3",
pages = "1362--1368",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}