Mn2+ Directly Activates cGAS and Structural Analysis Suggests Mn2+ Induces a Noncanonical Catalytic Synthesis of 2'3'-cGAMP.
Mn2+ Directly Activates cGAS and Structural Analysis Suggests Mn2+ Induces a Noncanonical Catalytic Synthesis of 2'3'-cGAMP.
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DOI：
10.1016/j.celrep.2020.108053
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发表时间：
2020-08
期刊：
影响因子：
8.8
通讯作者：
Zhen Zhao;Zhixing Ma;Bo Wang;Yukun Guan;X. Su;Zhengfan Jiang
中科院分区：
文献类型：
--
作者：
Zhen Zhao;Zhixing Ma;Bo Wang;Yukun Guan;X. Su;Zhengfan Jiang
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 η1 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 Mg2+, 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.
