Structures of Human ADAR2 Bound to DsRNA Reveal Base-flipping Mechanism and Basis for Site Selectivity

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2016 Apr 12

PMID 27065196

Citations 118

Authors

Melissa M Matthews

Justin M Thomas

Yuxuan Zheng

Kiet Tran

Kelly J Phelps

Anna I Scott

Jocelyn Havel

Andrew J Fisher

Peter A Beal

Affiliations

Soon will be listed here.

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.

Citing Articles

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