ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase

My-Nuong Vo, Markus Terrey, Jeong Woong Lee, Bappaditya Roy, James J. Moresco, Litao Sun, Hongjun Fu, Qi Liu, Thomas G. Weber, John R. Yates, Kurt Fredrick, Paul Schimmel () and Susan L. Ackerman ()
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My-Nuong Vo: Scripps Research Institute
Markus Terrey: University of California San Diego
Jeong Woong Lee: The Jackson Laboratory
Bappaditya Roy: The Ohio State University
James J. Moresco: Scripps Research Institute
Litao Sun: Scripps Research Institute
Hongjun Fu: The Jackson Laboratory
Qi Liu: The Ohio State University
Thomas G. Weber: Dynamic Biosensors GmbH
John R. Yates: Scripps Research Institute
Kurt Fredrick: The Ohio State University
Paul Schimmel: Scripps Research Institute
Susan L. Ackerman: University of California San Diego

Nature, 2018, vol. 557, issue 7706, 510-515

Abstract: Abstract Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aars sti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, we identified Ankrd16, a gene that acts epistatically with the Aars sti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides. The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.

Date: 2018
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DOI: 10.1038/s41586-018-0137-8

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