| Literature DB >> 30007416 |
Wen Zhou1, Aaron T Whiteley1, Carina C de Oliveira Mann1, Benjamin R Morehouse1, Radosław P Nowak2, Eric S Fischer2, Nathanael S Gray2, John J Mekalanos3, Philip J Kranzusch4.
Abstract
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.Entities:
Keywords: STING; cGAS; innate immunity; structural biology
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Year: 2018 PMID： 30007416 PMCID： PMC6084792 DOI： 10.1016/j.cell.2018.06.026
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582