High-throughput mutagenesis reveals unique structural features of human ADAR1

SeHee Park, Erin E. Doherty, Yixuan Xie, Anil K. Padyana, Fang Fang, Yue Zhang, Agya Karki, Carlito B. Lebrilla, Justin B. Siegel and Peter A. Beal ()
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SeHee Park: University of California, Davis
Erin E. Doherty: University of California, Davis
Yixuan Xie: University of California, Davis
Anil K. Padyana: Agios Pharmaceuticals
Fang Fang: Viva Biotech Ltd.
Yue Zhang: University of California, Davis
Agya Karki: University of California, Davis
Carlito B. Lebrilla: University of California, Davis
Justin B. Siegel: University of California, Davis
Peter A. Beal: University of California, Davis

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Adenosine Deaminases that act on RNA (ADARs) are enzymes that catalyze adenosine to inosine conversion in dsRNA, a common form of RNA editing. Mutations in the human ADAR1 gene are known to cause disease and recent studies have identified ADAR1 as a potential therapeutic target for a subset of cancers. However, efforts to define the mechanistic effects for disease associated ADAR1 mutations and the rational design of ADAR1 inhibitors are limited by a lack of structural information. Here, we describe the combination of high throughput mutagenesis screening studies, biochemical characterization and Rosetta-based structure modeling to identify unique features of ADAR1. Importantly, these studies reveal a previously unknown zinc-binding site on the surface of the ADAR1 deaminase domain which is important for ADAR1 editing activity. Furthermore, we present structural models that explain known properties of this enzyme and make predictions about the role of specific residues in a surface loop unique to ADAR1.

Date: 2020
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DOI: 10.1038/s41467-020-18862-2

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