Journal
MOLECULAR CELL
Volume 51, Issue 2, Pages 226-235Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2013.05.022
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Funding
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- NIH [RO1-AI-093967, RO1-GM-079554]
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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.
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