Mn2+ Directly Activates cGAS and Structural Analysis Suggests Mn2+ Induces a Noncanonical Catalytic Synthesis of 2′3′-cGAMP

作者：Zhen Zhao, Zhixing Ma, Bo Wang, Yukun Guan, Xiao‐Dong Su, Zhengfan Jiang · 发表于：Cell Reports · 年份：2020 · DOI：10.1016/j.celrep.2020.108053 · 被引用次数：324 · 研究领域：interferon and immune responses、RNA Research and Splicing、RNA modifications and cancer

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 η1 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.