期刊
CELL
卷 174, 期 2, 页码 300-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.06.026
关键词
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资金
- Claudia Adams Barr Program for Innovative Cancer Research
- Richard and Susan Smith Family Foundation
- Charles H. Hood Foundation
- Cancer Research Institute CLIP Grant
- NIAID [AI-01845]
- NIH [NCI R01CA214608]
- Jane Coffin Childs Memorial Fund for Medical Research
- Cancer Research Institute/Eugene V. Weissman Fellow
- NIH T32 Cancer Immunology training grant [5T32CA207021-02]
- NIGMS [P41 GM103403]
- NIH-ORIP HEI grant [S10 RR029205]
- DOE Argonne National Laboratory Advanced Photon Source [DE-AC02-06CH11357]
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.
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