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Publication Abstract from PubMed

DNA binding allosterically activates the cytosolic DNA sensor cGAS (cyclic GMP-AMP [cGAMP] synthase) to synthesize 2'3'-cGAMP, using Mg(2+) as the metal cofactor that catalyzes two nucleotidyl-transferring reactions. We previously found that Mn(2+) potentiates cGAS activation, but the underlying mechanism remains unclear. Here, we report that Mn(2+) directly activates cGAS. Structural analysis reveals that Mn(2+)-activated cGAS undergoes globally similar conformational changes to DNA-activated cGAS but forms a unique eta1 helix to widen the catalytic pocket, allowing substrate entry and cGAMP synthesis. Strikingly, in Mn(2+)-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 Mg(2+), the two catalytic Mn(2+) are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues. Our findings thus uncover Mn(2+) as a cGAS activator that initiates noncanonical 2'3'-cGAMP synthesis.

Mn(2+) Directly Activates cGAS and Structural Analysis Suggests Mn(2+) Induces a Noncanonical Catalytic Synthesis of 2'3'-cGAMP.,Zhao Z, Ma Z, Wang B, Guan Y, Su XD, Jiang Z Cell Rep. 2020 Aug 18;32(7):108053. doi: 10.1016/j.celrep.2020.108053. PMID:32814054^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.