Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase Journal Article
| Authors: | Gao, P.; Ascano, M.; Wu, Y.; Barchet, W.; Gaffney, B. L.; Zillinger, T.; Serganov, A. A.; Liu, Y.; Jones, R. A.; Hartmann, G.; Tuschl, T.; Patel, D. J. |
| Article Title: | Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase |
| Abstract: | Recent studies identified cyclic GMP-AMP (cGAMP) as a metazoan second messenger triggering an interferon response. cGAMP is generated from GTP and ATP by cytoplasmic dsDNA sensor cGAMP synthase (cGAS). We combined structural, chemical, biochemical, and cellular assays to demonstrate that this second messenger contains G(2′,5′)pA and A(3′,5′)pG phosphodiester linkages, designated c[G(2′,5′)pA(3′,5′) p]. We show that, upon dsDNA binding, cGAS is activated through conformational transitions, resulting in formation of a catalytically competent and accessible nucleotide-binding pocket for generation of c[G(2′,5′)pA(3′, 5′)p]. We demonstrate that cyclization occurs in a stepwise manner through initial generation of 5′-pppG(2′,5′)pA prior to cyclization to c[G(2′,5′)pA(3′,5′)p], with the latter positioned precisely in the catalytic pocket. Mutants of cGAS dsDNA-binding or catalytic pocket residues exhibit reduced or abrogated activity. Our studies have identified c[G(2′,5′)pA(3′,5′)p] as a founding member of a family of metazoan 2′,5′-containing cyclic heterodinucleotide second messengers distinct from bacterial 3′,5′ cyclic dinucleotides. © 2013 Elsevier Inc. |
| Keywords: | nonhuman; bacteria (microorganisms); dna; conformational transition; catalysis; dna binding; mutant; metazoa; adenosine phosphate; cyclic gmp |
| Journal Title: | Cell |
| Volume: | 153 |
| Issue: | 5 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2013-05-23 |
| Start Page: | 1094 |
| End Page: | 1107 |
| Language: | English |
| DOI: | 10.1016/j.cell.2013.04.046 |
| PROVIDER: | scopus |
| PUBMED: | 23647843 |
| PMCID: | PMC4382009 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):2 - "Export Date: 1 July 2013" - "CODEN: CELLB" - "Source: Scopus" |
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