The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop

Cell Rep. 2014 Feb 13;6(3):421-30. doi: 10.1016/j.celrep.2014.01.003. Epub 2014 Jan 23.

Abstract

The presence of DNA in the cytoplasm is a danger signal that triggers immune and inflammatory responses. Cytosolic DNA binds to and activates cyclic GMP-AMP (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP binds to the adaptor protein STING and activates a signaling cascade that leads to the production of type I interferons and other cytokines. Here, we report the crystal structures of human cGAS in its apo form, representing its autoinhibited conformation as well as in its cGAMP- and sulfate-bound forms. These structures reveal switch-like conformational changes of an activation loop that result in the rearrangement of the catalytic site. The structure of DNA-bound cGAS reveals a complex composed of dimeric cGAS bound to two molecules of DNA. Functional analyses of cGAS mutants demonstrate that both the protein-protein interface and the two DNA binding surfaces are critical for cGAS activation. These results provide insights into the mechanism of DNA sensing by cGAS.

Publication types

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

MeSH terms

  • Animals
  • Apoproteins / chemistry
  • Apoproteins / metabolism
  • Catalytic Domain
  • Cyclic GMP / chemistry
  • Cyclic GMP / metabolism
  • Cytosol / metabolism*
  • DNA / chemistry
  • DNA / metabolism*
  • Enzyme Activation
  • Humans
  • Interferon-beta / metabolism
  • Ions
  • Ligands
  • Mice
  • Models, Molecular
  • Nucleotidyltransferases / chemistry*
  • Nucleotidyltransferases / metabolism*
  • Protein Structure, Secondary
  • Sulfates / metabolism

Substances

  • Apoproteins
  • Ions
  • Ligands
  • Sulfates
  • Interferon-beta
  • DNA
  • MB21D1 protein, human
  • Nucleotidyltransferases
  • Cyclic GMP

Associated data

  • PDB/4O67
  • PDB/4O68
  • PDB/4O69
  • PDB/4O6A