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.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Electronic address: xu.zhang@utsouthwestern.edu.
Xu
X
Zhang
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Jiaxi
J
Wu
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Fenghe
F
Du
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Hui
H
Xu
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Lijun
L
Sun
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Zhe
Z
Chen
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Chad A
CA
Brautigam
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Xuewu
X
Zhang
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Electronic address: zhijian.chen@utsouthwestern.edu.
Zhijian J
ZJ
Chen
D000818:Animals; D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D006152:Cyclic GMP / Q000737:chemistry / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D007477:Ions; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009713:Nucleotidyltransferases / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D013431:Sulfates / Q000378:metabolism; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
D001059:Apoproteins; D006152:Cyclic GMP; D004247:DNA; D016899:Interferon-beta; D007477:Ions; D008024:Ligands; D009713:Nucleotidyltransferases; D013431:Sulfates; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase