Alternative stable conformation capable of protein misinteraction links tRNA synthetase to peripheral neuropathy.
Alternative stable conformation capable of protein misinteraction links tRNA synthetase to peripheral neuropathy.
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DOI：
10.1093/nar/gkx455
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发表时间：
2017-07-27
影响因子：
14.9
通讯作者：
Yang XL
中科院分区：
文献类型：
--
作者：
Blocquel D;Li S;Wei N;Daub H;Sajish M;Erfurth ML;Kooi G;Zhou J;Bai G;Schimmel P;Jordanova A;Yang XL
虽然有多种氨基酰基- trna合成酶与沙科-玛丽-图斯病（CMT）有关，这表明了一种共同的机制，但在CMT引起的突变体中，酶活性的缺陷并不相同。蛋白质错误折叠是许多神经系统疾病发展的共同假设。它的过程通常包括最初蛋白质稳定性的降低，然后是随后的寡聚和聚集。在这里，我们研究了三种导致cmt的酪氨酸- trna合成酶（TyrRS或YARS）突变的结构效应。通过各种方法，我们发现这些突变不会引起蛋白质二级结构的改变，也不会对寡聚化状态和稳定性产生共同的影响。然而，所有的突变都提供了进入野生型酶所掩盖的表面的途径，而这种途径与蛋白质的错误相互作用有关。根据另一种CMT连接的tRNA合成酶的最新数据，我们认为tRNA合成酶家族与CMT有内在的可塑性，可以形成能够异常相互作用的替代稳定构象。
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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影响因子：
64.8
作者：
He W;Bai G;Zhou H;Wei N;White NM;Lauer J;Liu H;Shi Y;Dumitru CD;Lettieri K;Shubayev V;Jordanova A;Guergueltcheva V;Griffin PR;Burgess RW;Pfaff SL;Yang XL
通讯作者：
Yang XL
影响因子：
15.9
作者：
Motley, William W.;Talbot, Kevin;Fischbeck, Kenneth H.
通讯作者：
Fischbeck, Kenneth H.
影响因子：
16.6
作者：
Langer, Andreas;Hampel, Paul A.;Kaiser, Wolfgang;Knezevic, Jelena;Welte, Thomas;Villa, Valentina;Maruyama, Makiko;Svejda, Matej;Jaehner, Simone;Fischer, Frank;Strasser, Ralf;Rant, Ulrich
通讯作者：
Rant, Ulrich
影响因子：
4.8
作者：
Li, Sheng;Tsalkova, Tamara;Cheng, Xiaodong
通讯作者：
Cheng, Xiaodong
影响因子：
6.1
作者：
Konarev, PV;Volkov, VV;Svergun, DI
通讯作者：
Svergun, DI