Structures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity

Melissa M. Matthews, Justin M. Thomas, Yuxuan Zheng, Kiet Tran, Kelly J. Phelps, Anna I. Scott, Jocelyn Havel, Andrew J Fisher, Peter A. Beal

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Adenosine deaminases acting on RNA (ADARs) are editing enzymes that convert adenosine to inosine in duplex RNA, a modification reaction with wide-ranging consequences in RNA function. Understanding of the ADAR reaction mechanism, the origin of editing-site selectivity, and the effect of mutations is limited by the lack of high-resolution structural data for complexes of ADARs bound to substrate RNAs. Here we describe four crystal structures of the human ADAR2 deaminase domain bound to RNA duplexes bearing a mimic of the deamination reaction intermediate. These structures, together with structure-guided mutagenesis and RNA-modification experiments, explain the basis of the ADAR deaminase domain's dsRNA specificity, its base-flipping mechanism, and its nearest-neighbor preferences. In addition, we identified an ADAR2-specific RNA-binding loop near the enzyme active site, thus rationalizing differences in selectivity observed between different ADARs. Finally, our results provide a structural framework for understanding the effects of ADAR mutations associated with human disease.

Original languageEnglish (US)
Pages (from-to)426-433
Number of pages8
JournalNature Structural and Molecular Biology
Volume23
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Matthews, M. M., Thomas, J. M., Zheng, Y., Tran, K., Phelps, K. J., Scott, A. I., Havel, J., Fisher, A. J., & Beal, P. A. (2016). Structures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity. Nature Structural and Molecular Biology, 23(5), 426-433. https://doi.org/10.1038/nsmb.3203