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

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

Wen Zhou, Aaron T Whiteley, Carina C de Oliveira Mann, Benjamin R Morehouse, Radosław P Nowak, Eric S Fischer, Nathanael S Gray, John J Mekalanos, Philip J Kranzusch

Cell. 2018 Jul 12;174(2):300-311.e11.

PMID: 30007416

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42417921	RPTPg Active human			Price
IAR4245700	PDE4A1A Active human			Price

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