Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High-Affinity Ligand for STING

被引:870
作者
Zhang, Xu [1 ]
Shi, Heping [2 ]
Wu, Jiaxi [1 ]
Zhang, Xuewu [3 ]
Sun, Lijun [1 ,4 ]
Chen, Chuo [2 ]
Chen, Zhijian J. [1 ,4 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
[3] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA
[4] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA
关键词
DI-GMP; SIGNALING PROTEIN; RECOGNITION; IDENTIFICATION; REVEALS; SENSOR;
D O I
10.1016/j.molcel.2013.05.022
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:226 / 235
页数:10
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