Structural Analysis of the STING Adaptor Protein Reveals a Hydrophobic Dimer Interface and Mode of Cyclic di-GMP Binding

Immunity. 2012 Jun 29;36(6):1073-86. doi: 10.1016/j.immuni.2012.03.019. Epub 2012 May 10.

Abstract

STING is an essential signaling molecule for DNA and cyclic di-GMP (c-di-GMP)-mediated type I interferon (IFN) production via TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway. It contains an N-terminal transmembrane region and a cytosolic C-terminal domain (CTD). Here, we describe crystal structures of STING CTD alone and complexed with c-di-GMP in a unique binding mode. The strictly conserved aa 153-173 region was shown to be cytosolic and participated in dimerization via hydrophobic interactions. The STING CTD functions as a dimer and the dimerization was independent of posttranslational modifications. Binding of c-di-GMP enhanced interaction of a shorter construct of STING CTD (residues 139-344) with TBK1. This suggests an extra TBK1 binding site, other than serine 358. This study provides a glimpse into the unique architecture of STING and sheds light on the mechanism of c-di-GMP-mediated TBK1 signaling.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Conserved Sequence
  • Crystallography, X-Ray
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • Dimerization
  • HEK293 Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Mapping
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship

Substances

  • Membrane Proteins
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • STING protein, human
  • bis(3',5')-cyclic diguanylic acid
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • Cyclic GMP

Associated data

  • PDB/4EF4
  • PDB/4EF5