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

Nature
My-Nuong VoSusan L Ackerman

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.

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Nov 15, 2018·Physiological Reviews·Hieronim Jakubowski
Aug 16, 2019·Wiley Interdisciplinary Reviews. RNA·Ofri LeviYoav Arava
Dec 22, 2019·The Journal of Biological Chemistry·Nien-Ching HanMichael Ibba
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Dec 16, 2020·RNA Biology·Han ZhangLitao Sun
Dec 20, 2018·Lancet Neurology·Kenneth S Kosik

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Methods Mentioned

BETA
aminoacylation
PCR
transgenic
co-IP
immunoprecipitation
affinity-capture
deacylation
thermal shift
fluorescence-activated cell sorting
fluorescence microscopy

Software Mentioned

GraphPad Prism
Dynamics Image Quant
Protein Thermal Shift
switchANALYSIS
ProLuCID
PyMOL
MudPIT
RawExtract
Patchdock
Molecular

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