Structures of Human ADAR2 Bound to DsRNA Reveal Base-flipping Mechanism and Basis for Site Selectivity
Author | : |
Publisher | : |
Total Pages | : 8 |
Release | : 2016 |
ISBN-10 | : OCLC:986214632 |
ISBN-13 | : |
Rating | : 4/5 (32 Downloads) |
Download or read book Structures of Human ADAR2 Bound to DsRNA Reveal Base-flipping Mechanism and Basis for Site Selectivity written by and published by . This book was released on 2016 with total page 8 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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. In this paper, 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. In conclusion, our results provide a structural framework for understanding the effects of ADAR mutations associated with human disease.