Asymmetric dimerization of adenosine deaminase acting on RNA facilitates substrate recognition.

Autor:	Thuy-Boun AS; Department of Chemistry, University of California, Davis, CA, USA., Thomas JM; Department of Chemistry, University of California, Davis, CA, USA., Grajo HL; Department of Chemistry, University of California, Davis, CA, USA., Palumbo CM; Department of Chemistry, University of California, Davis, CA, USA., Park S; Department of Chemistry, University of California, Davis, CA, USA., Nguyen LT; Department of Chemistry, University of California, Davis, CA, USA., Fisher AJ; Department of Chemistry, University of California, Davis, CA, USA.; Department of Molecular and Cellular Biology, University of California, Davis, CA, USA., Beal PA; Department of Chemistry, University of California, Davis, CA, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2020 Aug 20; Vol. 48 (14), pp. 7958-7972.
DOI:	10.1093/nar/gkaa532
Abstrakt:	Adenosine deaminases acting on RNA (ADARs) are enzymes that convert adenosine to inosine in duplex RNA, a modification that exhibits a multitude of effects on RNA structure and function. Recent studies have identified ADAR1 as a potential cancer therapeutic target. ADARs are also important in the development of directed RNA editing therapeutics. A comprehensive understanding of the molecular mechanism of the ADAR reaction will advance efforts to develop ADAR inhibitors and new tools for directed RNA editing. Here we report the X-ray crystal structure of a fragment of human ADAR2 comprising its deaminase domain and double stranded RNA binding domain 2 (dsRBD2) bound to an RNA duplex as an asymmetric homodimer. We identified a highly conserved ADAR dimerization interface and validated the importance of these sequence elements on dimer formation via gel mobility shift assays and size exclusion chromatography. We also show that mutation in the dimerization interface inhibits editing in an RNA substrate-dependent manner for both ADAR1 and ADAR2. (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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