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PDBsum entry 5thh
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References listed in PDB file
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Key reference
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Title
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Alternative stable conformation capable of protein misinteraction links tRNA synthetase to peripheral neuropathy.
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Authors
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D.Blocquel,
S.Li,
N.Wei,
H.Daub,
M.Sajish,
M.L.Erfurth,
G.Kooi,
J.Zhou,
G.Bai,
P.Schimmel,
A.Jordanova,
X.L.Yang.
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Ref.
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Nucleic Acids Res, 2017,
45,
8091-8104.
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PubMed id
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Abstract
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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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