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. Epub 2019 Mar 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoproteins / chemistry
  • Apoproteins / metabolism
  • Apoproteins / ultrastructure
  • Chickens*
  • Cryoelectron Microscopy*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Membrane Proteins / ultrastructure*
  • Models, Molecular
  • Nucleotides, Cyclic / chemistry
  • Nucleotides, Cyclic / metabolism*

Substances

  • Apoproteins
  • Membrane Proteins
  • Nucleotides, Cyclic
  • STING protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate