The DOI matches its Crossref record; 17 of the 17 references it cites were found in a registry or an index.
Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance
Open accessAbstract
Summary Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS-DNA complex provide a model for enzyme activation, but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP-AMP (cGAMP) synthesis compared to other mammals. Here we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity, and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity, and provide a model of the active human cGAS-DNA complex to enable structure-guided design of cGAS therapeutics. eTOC Blurb The structure of the human cGAS–DNA complex reveals regulatory adaptations that balance enzymatic activity with DNA-length sensitivity, and additional features important for drug design.
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Cited by
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Metadata
- Authors
- Zhou, W., Whiteley, A. T., de Oliveira Mann, C. C., Morehouse, B. R., Nowak, R. P., Fischer, E. S., Gray, N. S., Mekalanos, J. J., & Kranzusch, P. J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 174
- Issue
- 2
- Pages
- 300-311.e11
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2884661296
- Cited by
- 387
- References
- 17
- FWCI
- 10.03
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Zhou, W., Whiteley, A. T., de Oliveira Mann, C. C., Morehouse, B. R., Nowak, R. P., Fischer, E. S., Gray, N. S., Mekalanos, J. J., & Kranzusch, P. J. (2018). Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance. Cell. https://doi.org/10.1016/j.cell.2018.06.026
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