Structures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity
Journal Article
·
· Nature Structural & Molecular Biology
- Univ. of California, Davis, CA (United States). Dept. of Chemistry
- Univ. of California, Davis, CA (United States). Dept. of Molecular and Cellular Biology
- Univ. of California, Davis, CA (United States). Dept. of Chemistry. Dept. of Molecular and Cellular Biology
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.
- Research Organization:
- Univ. of California, Davis, CA (United States)
- Sponsoring Organization:
- National Inst. of Health (NIH) (United States); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
- Grant/Contract Number:
- AC02-06CH11357; AC02-76SF00515
- OSTI ID:
- 1255288
- Journal Information:
- Nature Structural & Molecular Biology, Journal Name: Nature Structural & Molecular Biology Journal Issue: 5 Vol. 23; ISSN 1545-9993
- Publisher:
- Nature Publishing GroupCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
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