Allosteric coupling between Mn2+ and dsDNA controls the catalytic efficiency and fidelity of cGAS. Issue 8 (14th March 2020)

• Record Type: Journal Article
• Authors: Hooy, Richard M; Massaccesi, Guido; Rousseau, Kimberly E; Chattergoon, Michael A; Sohn, Jungsan
• Is Part Of: Nucleic acids research. Volume 48:Issue 8(2020)
• Page Start: 4435
• Page End: 4447
• Publication Date: 2020-03-14
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkaa084
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Cyclic-G/AMP (cGAMP) synthase (cGAS) triggers host innate immune responses against cytosolic double-stranded (ds)DNA arising from genotoxic stress and pathogen invasion. The canonical activation mechanism of cGAS entails dsDNA-binding and dimerization. Here, we report an unexpected activation mechanism of cGAS in which Mn 2+ activates monomeric cGAS without dsDNA. Importantly, the Mn 2+ -mediated activation positively couples with dsDNA-dependent activation in a concerted manner. Moreover, the positive coupling between Mn 2+ and dsDNA length-dependent activation requires the cognate ATP/GTP substrate pair, while negative-cooperativity suppresses Mn 2+ utilization by either ATP or GTP alone. Additionally, while Mn 2+ accelerates the overall catalytic activity, dsDNA length-dependent dimerization specifically accelerates the cyclization of cGAMP. Together, we demonstrate how the intrinsic allostery of cGAS efficiently yet precisely tunes its activity.