Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP

  • Nature. 2019 Mar;567(7748):389-393. doi: 10.1038/s41586-019-0998-5.
Guijun Shang  1 ,  Conggang Zhang  2 ,  Zhijian J Chen  3  4  5 ,  Xiao-Chen Bai  6  7 ,  Xuewu Zhang  8  9
Affiliations
  • 1. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 4. Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 5. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 6. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 7. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 8. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 9. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
PMID: 30842659 DOI: 10.1038/s41586-019-0998-5
Abstract

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.