Inositol Hexakisphosphate Is Bound in the ADAR2 Core and Required for RNA Editing

Abstract

We report the crystal structure of the catalytic domain of human ADAR2, an RNA editing enzyme, at 1.7 angstrom resolution. The structure reveals a zinc ion in the active site and suggests how the substrate adenosine is recognized. Unexpectedly, inositol hexakisphosphate (IP 6 ) is buried within the enzyme core, contributing to the protein fold. Although there are no reports that adenosine deaminases that act on RNA (ADARs) require a cofactor, we show that IP 6 is required for activity. Amino acids that coordinate IP 6 in the crystal structure are conserved in some adenosine deaminases that act on transfer RNA (tRNA) (ADATs), related enzymes that edit tRNA. Indeed, IP 6 is also essential for in vivo and in vitro deamination of adenosine 37 of tRNA ala by ADAT1.