7BUJ

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

(2020) Cell Rep 32: 108053-108053

• PubMed: 32814054 Search on PubMed
• DOI: https://doi.org/10.1016/j.celrep.2020.108053
• Primary Citation of Related Structures:  
  7BUJ, 7BUM, 7BUQ


• PubMed Abstract: 
  

  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.

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Organizational Affiliation: 

Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.