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The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop

Open access
Zhang, Xu, Wu, Jiaxi, Du, Fenghe, Xu, Hui, Sun, Lijun, Chen, Zhe, Brautigam, Chad A., Zhang, Xuewu, Chen, Zhijian J.·2014·Cell Reports

Abstract

The presence of DNA in the cytoplasm is a danger signal that triggers immune and inflammatory responses. Cytosolic DNA binds to and activates cyclic GMP-AMP (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP binds to the adaptor protein STING and activates a signaling cascade that leads to the production of type I interferons and other cytokines. Here, we report the crystal structures of human cGAS in its apo form, representing its autoinhibited conformation as well as in its cGAMP- and sulfate-bound forms. These structures reveal switch-like conformational changes of an activation loop that result in the rearrangement of the catalytic site. The structure of DNA-bound cGAS reveals a complex composed of dimeric cGAS bound to two molecules of DNA. Functional analyses of cGAS mutants demonstrate that both the protein-protein interface and the two DNA binding surfaces are critical for cGAS activation. These results provide insights into the mechanism of DNA sensing by cGAS.

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Metadata

Authors
Zhang, X., Wu, J., Du, F., Xu, H., Sun, L., Chen, Z., Brautigam, C. A., Zhang, X., & Chen, Z. J.
Venue
Cell Reports
Publisher
Elsevier BV
Published
2014-02
Volume
6
Issue
3
Pages
421-430
ISSN
2211-1247 (ISSN-L)
OpenAlex
W2134644569
Cited by
510
References
5
FWCI
10.24
Type
journal article
Language
en
Open access
gold

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CoChat. (2026). Citation check: The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop. https://app.cochat.ai/papers/10.1016/j.celrep.2014.01.003
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Zhang, X., Wu, J., Du, F., Xu, H., Sun, L., Chen, Z., Brautigam, C. A., Zhang, X., & Chen, Z. J. (2014). The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop. Cell Reports. https://doi.org/10.1016/j.celrep.2014.01.003

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