Cyclic di-GMP sensing via the innate immune signaling protein STING

Mol Cell. 2012 Jun 29;46(6):735-45. doi: 10.1016/j.molcel.2012.05.029. Epub 2012 Jun 14.

Abstract

Detection of foreign materials is the first step of successful immune responses. Stimulator of interferon genes (STING) was shown to directly bind cyclic diguanylate monophosphate (c-di-GMP), a bacterial second messenger, and to elicit strong interferon responses. Here we elucidate the structural features of the cytosolic c-di-GMP binding domain (CBD) of STING and its complex with c-di-GMP. The CBD exhibits an α + β fold and is a dimer in the crystal and in solution. Surprisingly, one c-di-GMP molecule binds to the central crevice of a STING dimer, using a series of stacking and hydrogen bonding interactions. We show that STING is autoinhibited by an intramolecular interaction between the CBD and the C-terminal tail (CTT) and that c-di-GMP releases STING from this autoinhibition by displacing the CTT. The structures provide a remarkable example of pathogen-host interactions in which a unique microbial molecule directly engages the innate immune system.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • Dimerization
  • Humans
  • Hydrogen Bonding
  • Immunity, Innate*
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Signal Transduction / immunology*

Substances

  • Membrane Proteins
  • STING protein, human
  • bis(3',5')-cyclic diguanylic acid
  • Cyclic GMP

Associated data

  • PDB/4F9E
  • PDB/4F9G