The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop

The presence of DNA in the cytoplasm is a danger signal that triggers immune and inflammatory responses. Cytosolic DNA binds to and activates cyclic GMP-AMP (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP binds to the adaptor protein STING and activates a signaling cascade that leads to the production of type I interferons and other cytokines. Here, we report the crystal structures of human cGAS in its apo form, representing its autoinhibited conformation as well as in its cGAMP- and sulfate-bound forms. These structures reveal switch-like conformational changes of an activation loop that result in the rearrangement of the catalytic site. The structure of DNA-bound cGAS reveals a complex composed of dimeric cGAS bound to two molecules of DNA. Functional analyses of cGAS mutants demonstrate that both the protein-protein interface and the two DNA binding surfaces are critical for cGAS activation. These results provide insights into the mechanism of DNA sensing by cGAS. [Display omitted] •DNA binding switches an activation loop in cGAS•DNA binding induces dimerization of cGAS, forming a 2:2 complex•cGAS dimerization is essential for its activation•The two cGAS DNA binding surfaces are critical for inducing type I interferons cGAS is a recently discovered cytosolic DNA sensor that induces type I interferons by producing the second messenger cyclic GMP-AMP (cGAMP). Zhang, Chen, and colleagues now determine the structures of cGAS in the presence and absence of DNA and find that DNA binding induces cGAS dimerization, which is necessary for activation. The authors also identify an activation loop of cGAS that plays a critical role in triggering the rearrangement of the active site in response to DNA binding.