Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING

Mol Cell. 2013 Jul 25;51(2):226-35. doi: 10.1016/j.molcel.2013.05.022. Epub 2013 Jun 6.

Abstract

The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biosensing Techniques
  • Crystallography, X-Ray
  • Cyclic AMP / chemistry
  • Cyclic AMP / metabolism*
  • Cyclic GMP / chemistry
  • Cyclic GMP / metabolism*
  • DNA / chemistry
  • DNA / genetics
  • DNA / metabolism*
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nucleotidyltransferases / chemistry*
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism
  • Protein Conformation
  • Second Messenger Systems*
  • Tandem Mass Spectrometry

Substances

  • Membrane Proteins
  • STING protein, human
  • DNA
  • Cyclic AMP
  • MB21D1 protein, human
  • Nucleotidyltransferases
  • Cyclic GMP

Associated data

  • PDB/4KSY