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

• Wen Zhou ^[1] ; Aaron T. Whiteley ^[1] ; Carina C. de Oliveira Mann ^[1]
  1. [1] Harvard Medical School

     Harvard Medical School

     City of Boston, Estados Unidos

     
• Localización: Cell, ISSN 0092-8674, Vol. 174, Nº. 2, 2018, págs. 300-311
• Idioma: inglés
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• Resumen

  • 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.