Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance

Anonymous — Thu, 12 Jul 2018 06:00:00 +0000

Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance Anonymous (not verified) Thu, 07/12/2018 - 00:00

Zhou W* ➤Whiteley AT* de Oliveira Mann CC Morehouse BR Nowak RP Fischer ES Gray NS Mekalanos JJ Kranzusch PJ

*These authors contributed equally to this work

Cell. 2018 Jul 12;174(2):300-311.e11. doi: 10.1016/j.cell.2018.06.026.

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.

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Human cGAS Has a Slightly Different Taste for dsDNA. [Immunity. 2018]

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Zhou W*, ➤Whiteley AT*, de Oliveira Mann CC, Morehouse BR, Nowak RP, Fischer ES, Gray NS, Mekalanos JJ, Kranzusch PJ. | Cell. 2018

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Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance

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