Journal
CELL REPORTS
Volume 32, Issue 7, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108053
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Funding
- Chinese Ministry of Science and Technology [2019YFA0508500, 2016YFC0906000]
- National Natural Science Foundation of China [31830022, 81621001]
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DNA binding allosterically activates the cytosolic DNA sensor cGAS (cyclic GMP-AMP [cGAMP] synthase) to synthesize 2'3'-cGAMP, using Mg2+ as the metal cofactor that catalyzes two nucleotidyl-transferring reactions. We previously found that Mn2+ potentiates cGAS activation, but the underlying mechanism remains unclear, Here, we report that Mn2+ directly activates cGAS. Structural analysis reveals that Mn2+-activated cGAS undergoes globally similar conformational changes to DNA-activated cGAS but forms a unique eta 1 helix to widen the catalytic pocket, allowing substrate entry and cGAMP synthesis. Strikingly, in Mn2+-activated cGAS, the linear intermediates pppGpG and pGpA take an inverted orientation in the active pocket, suggesting a noncanonical but accelerated cGAMP cyclization without substrate flip-over. Moreover. unlike the octahedral coordination around Mn2+, the two catalytic Mn2+ are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues. Our findings thus uncover Mn2+ as a cGAS activator that initiates noncanonical 2'3'-cGAMP synthesis.
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