2. Academic Validation
  3. 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

  • Cell. 2018 Jul 12;174(2):300-311.e11. doi: 10.1016/j.cell.2018.06.026.
Wen Zhou 1,  Aaron T Whiteley 1,  Carina C de Oliveira Mann 1,  Benjamin R Morehouse 1,  Radosław P Nowak 2,  Eric S Fischer 2,  Nathanael S Gray 2,  John J Mekalanos 3,  Philip J Kranzusch 4
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 3 Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: philip_kranzusch@dfci.harvard.edu.
PMID: 30007416 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.

Keywords

STING; cGAS; innate immunity; structural biology.

Figures