| First Author | Zhou W | Year | 2018 |
| Journal | Cell | Volume | 174 |
| Issue | 2 | Pages | 300-311.e11 |
| PubMed ID | 30007416 | Mgi Jnum | J:268008 |
| Mgi Id | MGI:6270846 | Doi | 10.1016/j.cell.2018.06.026 |
| Citation | Zhou W, et al. (2018) Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance. Cell 174(2):300-311.e11 |
| abstractText | 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. |
