title: Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING.
abstract: The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Heping
authors.initials: H
authors.lastname: Shi
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Wu
authors.forename: Xuewu
authors.initials: X
authors.lastname: Zhang
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D015374:Biosensing Techniques; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism*; D006152:Cyclic GMP / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D015290:Second Messenger Systems; D053719:Tandem Mass Spectrometry; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D000242:Cyclic AMP; D006152:Cyclic GMP; D004247:DNA; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C532857:STING1 protein, human; D000099197:STING Protein; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase