The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop
Open accessAbstract
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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Cites
[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling
Ishikawa, H., & Barber, G. N. (2008) · Nature · doi:10.1038/nature07317 · Cited by 3,576
CGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING.
Ablasser, A., Goldeck, M., Cavlar, T., Deimling, T., Witte, G., Röhl, I., Hopfner, K.-P., Ludwig, J., & Hornung, V. (2013) · Nature · doi:10.1038/nature12306 · Cited by 1,695
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RIGorous Detection: Exposing Virus Through RNA Sensing
Rehwinkel, J., & Reis e Sousa, C. (2010) · Science · doi:10.1126/science.1185068 · Cited by 163
Cited by
Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing
Chen, Q., Sun, L., & Chen, Z. J. (2016) · Nature Immunology · doi:10.1038/ni.3558 · Cited by 2,333
Self-citationThe cGAS–STING pathway as a therapeutic target in inflammatory diseases
Decout, A., Katz, J. D., Venkatraman, S., & Ablasser, A. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00524-z · Cited by 2,309
Molecular mechanisms and cellular functions of cGAS–STING signalling
Hopfner, K.-P., & Hornung, V. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0244-x · Cited by 2,052
cGAS surveillance of micronuclei links genome instability to innate immunity
Mackenzie, K. J., Carroll, P., Martin, C.-A., Murina, O., Fluteau, A., Simpson, D. J., Olova, N., Sutcliffe, H., Rainger, J. K., Leitch, A., et al. (2017) · Nature · doi:10.1038/nature23449 · Cited by 1,752
Mechanisms of action of hydroxychloroquine and chloroquine:implications for rheumatology
Schrezenmeier, E., & Dörner, T. (2020) · Nature Reviews Rheumatology · doi:10.1038/s41584-020-0372-x · Cited by 1,468
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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