TY - JOUR
T1 - Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP
AU - Shang, Guijun
AU - Zhang, Conggang
AU - Chen, Zhijian J.
AU - Bai, Xiao chen
AU - Zhang, Xuewu
N1 - Funding Information:
Acknowledgements We thank Hongtao Yu and Ryan Hibbs for sharing intruments and reagents, and Xiang Gui for his contributions on the analysis of some STING mutants. Cryo-EM data were collected at the University of Texas Southwestern Medical Center (UTSW) Cryo-Electron Microscopy Facility, which is funded by the Cancer Prevention and Research Institute of Texas (CPRIT) Core Facility Support Award RP170644. We thank D. Nicastro for facility access and data acquisition. This work is supported in part by the Howard Hughes Medical Institute (Z.J.C.), grants from the National Institutes of Health (GM088197 and R35GM130289 to X.Z.), grants from the Welch foundation (I-1389 to Z.J.C.; I-1702 to X.Z.; I-1944 to X.-c.B.), grants from CPRIT (RP150498 to Z.J.C.; RP160082 to X.-c.B.). X.-c.B. and X.Z. are Virginia Murchison Linthicum Scholars in Medical Research at UTSW. Z.J.C. is an investigator of Howard Hughes Medical Institute.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/3/21
Y1 - 2019/3/21
N2 - Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP–AMP synthase, which produces 2′3′-cyclic GMP–AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS)1–8. STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain9–13. The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP9,14. However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.
AB - Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP–AMP synthase, which produces 2′3′-cyclic GMP–AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS)1–8. STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain9–13. The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP9,14. However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.
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U2 - 10.1038/s41586-019-0998-5
DO - 10.1038/s41586-019-0998-5
M3 - Article
C2 - 30842659
AN - SCOPUS:85063003311
VL - 567
SP - 389
EP - 393
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7748
ER -