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Mn2+ Directly Activates cGAS and Structural Analysis Suggests Mn2+ Induces a Noncanonical Catalytic Synthesis of 2′3′-cGAMP
Open accessAbstract
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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Metadata
- Authors
- Zhao, Z., Ma, Z., Wang, B., Guan, Y., Su, X.-D., & Jiang, Z.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 32
- Issue
- 7
- Pages
- 108053
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W3077216535
- Cited by
- 328
- References
- 50
- FWCI
- 8.60
- Type
- journal article
- Language
- en
- Open access
- gold
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- Zhao, Z., Ma, Z., Wang, B., Guan, Y., Su, X.-D., & Jiang, Z. (2020). Mn2+ Directly Activates cGAS and Structural Analysis Suggests Mn2+ Induces a Noncanonical Catalytic Synthesis of 2′3′-cGAMP. Cell Reports. https://doi.org/10.1016/j.celrep.2020.108053
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