NMR Dynamics Study Reveals the Zα Domain of Human ADAR1 Associates with and Dissociates from Z-RNA More Slowly than Z-DNA.

Human RNA editing enzyme ADAR1 deaminates adenosine in pre-mRNA to yield inosine. The Zα domain of human ADAR1 (hZα) binds specifically to left-handed Z-RNA as well as Z-DNA and stabilizes the Z-conformation. To answer the question of how hZα can induce both the B-Z transition of DNA and the A-Z transition of RNA, we investigated the structure and dynamics of hZα in complex with 6-base-pair Z-DNA or Z-RNA. We performed chemical shift perturbation and relaxation dispersion experiments on hZα upon binding to Z-DNA as well as Z-RNA. Our study demonstrates the unique dynamics of hZα during the A-Z transition of RNA, in which the hZα protein forms a thermodynamically stable complex with Z-RNA, similar to Z-DNA, but kinetically converts RNA to the Z-form more slowly than DNA. We also discovered some distinct structural features of hZα in the Z-RNA binding conformation. Our results suggest that the A-Z transition of RNA facilitated by hZα displays unique structural and dynamic features that may be involved in targeting ADAR1 for a role in recognition of RNA substrates.