Blocquel David, Li Sheng, Wei Na, Daub Herwin, Sajish Mathew, Erfurth Maria-Luise, Kooi Grace, Zhou Jiadong, Bai Ge, Schimmel Paul, Jordanova Albena, Yang Xiang-Lei
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
Nucleic Acids Res. 2017 Jul 27;45(13):8091-8104. doi: 10.1093/nar/gkx455.
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.
虽然多种氨酰-tRNA合成酶与夏科-马里-图斯病（CMT）相关，这表明存在一种共同机制，但导致CMT的突变体之间不存在酶活性缺陷。蛋白质错误折叠是许多神经疾病发生的一个常见假说。其过程通常涉及蛋白质稳定性的最初降低，随后是寡聚化和聚集。在这里，我们研究了酪氨酰-tRNA合成酶（TyrRS或YARS）中三个导致CMT的突变的结构效应。通过各种方法，我们发现这些突变不会诱导蛋白质二级结构的变化，也不会对寡聚化状态和稳定性产生共同影响。然而，所有突变都会暴露野生型酶中被掩盖的一个表面，且这种暴露与蛋白质错误相互作用相关。结合最近关于另一种与CMT相关的tRNA合成酶的数据，我们认为一种内在的可塑性，即形成能够发生异常相互作用的替代稳定构象，将tRNA合成酶家族与CMT联系起来。
