Alternative stable conformation capable of protein misinteraction links tRNA synthetase to peripheral neuropathy

Nucleic Acids Research
David BlocquelXiang-Lei Yang

Abstract

While having multiple aminoacyl-tRNA synthetases implicated in Charcot-Marie-Tooth (CMT) disease suggests a common mechanism, a defect in enzymatic activity is not shared among the CMT-causing mutants. Protein misfolding is a common hypothesis underlying the development of many neurological diseases. Its process usually involves an initial reduction in protein stability and then the subsequent oligomerization and aggregation. Here, we study the structural effect of three CMT-causing mutations in tyrosyl-tRNA synthetase (TyrRS or YARS). Through various approaches, we found that the mutations do not induce changes in protein secondary structures, or shared effects on oligomerization state and stability. However, all mutations provide access to a surface masked in the wild-type enzyme, and that access correlates with protein misinteraction. With recent data on another CMT-linked tRNA synthetase, we suggest that an inherent plasticity, engendering the formation of alternative stable conformations capable of aberrant interactions, links the tRNA synthetase family to CMT.

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Citations

Jun 22, 2017·Human Molecular Genetics·Rebecca Meyer-Schuman, Anthony Antonellis
Dec 31, 2017·FEBS Letters·Veronika BoczonadiRita Horvath
Sep 11, 2019·Proceedings of the National Academy of Sciences of the United States of America·David BlocquelXiang-Lei Yang
Jul 25, 2018·Nature Reviews. Molecular Cell Biology·Soroush TahmasebiNahum Sonenberg
Jul 28, 2018·Acta Neuropathologica Communications·Emilie L CastranioRadosveta Koldamova
Nov 26, 2020·Journal of Neurochemistry·Han ZhangLitao Sun
Jan 1, 2021·Frontiers in Neurology·Yongzhi XieRuxu Zhang
Mar 24, 2021·Proceedings of the National Academy of Sciences of the United States of America·Litao SunXiang-Lei Yang
Apr 9, 2021·Biochemistry. Biokhimii︠a︡·Ekaterina S VinogradovaEkaterina Yu Nikonova
Aug 17, 2021·Frontiers in Molecular Biosciences·Elisabeth LataMartin Teichmann

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Methods Mentioned

BETA
aminoacylation
transgenic
PCR
gel filtrations
gel filtration
circular dichroism
thermal shift
X-ray
biosensor
biolayer interferometry

Software Mentioned

PRIMUS
ProtParam
Proteom Discoverer
UCSF Chimera
DAMAVER
GNOM
Octet
DAMMIF
Protein Thermal [UNK]

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