Structure of Human cGAS Reveals a Conserved Family of Second-Messenger Enzymes in Innate Immunity

PhilipJ Kranzusch, AmySi Ying Lee, James M Berger, JenniferA Doudna

Research output: Contribution to journalArticle

Abstract

Innate immune recognition of foreign nucleic acids induces protective interferon responses. Detection of cytosolic DNA triggers downstream immune signaling through activation of cyclic GMP-AMP synthase (cGAS). We report here the crystal structure of human cGAS, revealing an unanticipated zinc-ribbon DNA-binding domain appended to a core enzymatic nucleotidyltransferase scaffold. The catalytic core of cGAS is structurally homologous to the RNA-sensing enzyme, 2'-5' oligo-adenylate synthase (OAS), and divergent C-terminal domains account for specific ligand-activation requirements of each enzyme. We show that the cGAS zinc ribbon is essential for STING-dependent induction of the interferon response and that conserved amino acids displayed within the intervening loops are required for efficient cytosolic DNA recognition. These results demonstrate that cGAS and OAS define a family of innate immunity sensors and that structural divergence from a core nucleotidyltransferase enables second-messenger responses to distinct foreign nucleic acids.

Original languageEnglish (US)
Pages (from-to)1362-1368
Number of pages7
JournalCell Reports
Volume3
Issue number5
DOIs
StatePublished - May 30 2013
Externally publishedYes

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GMP synthase (glutamine-hydrolyzing)
Second Messenger Systems
Innate Immunity
Nucleotidyltransferases
Enzymes
Nucleic Acids
Interferons
Zinc
DNA
Chemical activation
Scaffolds
Catalytic Domain
Crystal structure
RNA
Ligands
Amino Acids
cyclic guanosine monophosphate-adenosine monophosphate
human MB21D1 protein
Sensors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Structure of Human cGAS Reveals a Conserved Family of Second-Messenger Enzymes in Innate Immunity. / Kranzusch, PhilipJ; Lee, AmySi Ying; Berger, James M; Doudna, JenniferA.

In: Cell Reports, Vol. 3, No. 5, 30.05.2013, p. 1362-1368.

Research output: Contribution to journalArticle

Kranzusch, PhilipJ ; Lee, AmySi Ying ; Berger, James M ; Doudna, JenniferA. / Structure of Human cGAS Reveals a Conserved Family of Second-Messenger Enzymes in Innate Immunity. In: Cell Reports. 2013 ; Vol. 3, No. 5. pp. 1362-1368.
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