Structural mechanism of cytosolic DNA sensing by cGAS

Nature. 2013 Jun 20;498(7454):332-7. doi: 10.1038/nature12305. Epub 2013 May 30.

Abstract

Cytosolic DNA arising from intracellular bacterial or viral infections is a powerful pathogen-associated molecular pattern (PAMP) that leads to innate immune host defence by the production of type I interferon and inflammatory cytokines. Recognition of cytosolic DNA by the recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of cGAMP to activate the stimulator of interferon genes (STING). Here we report the crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies. Our results explain the broad DNA sensing specificity of cGAS, show how cGAS catalyses dinucleotide formation and indicate activation by a DNA-induced structural switch. cGAS possesses a remarkable structural similarity to the antiviral cytosolic double-stranded RNA sensor 2'-5'oligoadenylate synthase (OAS1), but contains a unique zinc thumb that recognizes B-form double-stranded DNA. Our results mechanistically unify dsRNA and dsDNA innate immune sensing by OAS1 and cGAS nucleotidyl transferases.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Animals
  • Base Sequence
  • Catalytic Domain
  • Crystallography, X-Ray
  • Cytosol*
  • DNA / chemistry
  • DNA / metabolism*
  • DNA / pharmacology
  • Guanosine Triphosphate / chemistry
  • Guanosine Triphosphate / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Models, Biological
  • Models, Molecular
  • Mutation
  • Nucleotidyltransferases / chemistry*
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism
  • Protein Conformation / drug effects
  • Structure-Activity Relationship
  • Substrate Specificity
  • Swine
  • Uridine Triphosphate / chemistry
  • Uridine Triphosphate / metabolism
  • Zinc / chemistry
  • Zinc / metabolism

Substances

  • MPYS protein, mouse
  • Membrane Proteins
  • Guanosine Triphosphate
  • Adenosine Triphosphate
  • DNA
  • MB21D1 protein, human
  • Nucleotidyltransferases
  • Zinc
  • Uridine Triphosphate

Associated data

  • PDB/4JLX
  • PDB/4JLZ
  • PDB/4KB6