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Inositol Hexakisphosphate Is Bound in the ADAR2 Core and Required for RNA Editing
Mark R. Macbeth,1,2Heidi L. Schubert,1Andrew P. VanDemark,1Arunth T. Lingam,1,2Christopher P. Hill,1*Brenda L. Bass1,2*
We report the crystal structure of the catalytic domain of humanADAR2, an RNA editing enzyme, at 1.7 angstrom resolution. Thestructure reveals a zinc ion in the active site and suggestshow the substrate adenosine is recognized. Unexpectedly, inositolhexakisphosphate (IP6) is buried within the enzyme core, contributingto the protein fold. Although there are no reports that adenosinedeaminases that act on RNA (ADARs) require a cofactor, we showthat IP6 is required for activity. Amino acids that coordinateIP6 in the crystal structure are conserved in some adenosinedeaminases that act on transfer RNA (tRNA) (ADATs), relatedenzymes that edit tRNA. Indeed, IP6 is also essential for invivo and in vitro deamination of adenosine 37 of tRNAala byADAT1.
1 Department of Biochemistry, University of Utah, Salt Lake City, UT 84132, USA. 2 Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84132, USA.
* To whom correspondence should be addressed. E-mail: bbass{at}howard.genetics.utah.edu (B.L.B.); chris{at}biochem.utah.edu (C.P.H.)
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