Rajendren, SubaManning, Aidan C.Al-Awadi, HaiderYamada, KentaroTakagi, YuichiroHundley, Heather A.2019-05-152019-05-152018-10-12Rajendren, S., Manning, A. C., Al-Awadi, H., Yamada, K., Takagi, Y., & Hundley, H. A. (2018). A protein-protein interaction underlies the molecular basis for substrate recognition by an adenosine-to-inosine RNA-editing enzyme. Nucleic acids research, 46(18), 9647–9659. doi:10.1093/nar/gky800https://hdl.handle.net/1805/19310Adenosine deaminases that act on RNA (ADARs) convert adenosine to inosine within double-stranded regions of RNA, resulting in increased transcriptomic diversity, as well as protection of cellular double-stranded RNA (dsRNA) from silencing and improper immune activation. The presence of dsRNA-binding domains (dsRBDs) in all ADARs suggests these domains are important for substrate recognition; however, the role of dsRBDs in vivo remains largely unknown. Herein, our studies indicate the Caenorhabditis elegans ADAR enzyme, ADR-2, has low affinity for dsRNA, but interacts with ADR-1, an editing-deficient member of the ADAR family, which has a 100-fold higher affinity for dsRNA. ADR-1 uses one dsRBD to physically interact with ADR-2 and a second dsRBD to bind to dsRNAs, thereby tethering ADR-2 to substrates. ADR-2 interacts with >1200 transcripts in vivo, and ADR-1 is required for 80% of these interactions. Our results identify a novel mode of substrate recognition for ADAR enzymes and indicate that protein-protein interactions can guide substrate recognition for RNA editors.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesAdenosine deaminasesRNAAdenosineInosineDouble-stranded RNAArticle