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Nat Struct Mol Biol. 2016 May;23(5):426-33. doi: 10.1038/nsmb.3203. Epub 2016 Apr 11.

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

Author information

1
Department of Chemistry, University of California, Davis, Davis, California, USA.
2
Department of Molecular and Cellular Biology, University of California, Davis, Davis, California, USA.

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.

PMID:
27065196
PMCID:
PMC4918759
DOI:
10.1038/nsmb.3203
[Indexed for MEDLINE]
Free PMC Article

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