Akoury Elias, Mukrasch Marco D, Biernat Jacek, Tepper Katharina, Ozenne Valery, Mandelkow Eckhard, Blackledge Martin, Zweckstetter Markus
Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany.
German Center for Neurodegenerative Diseases (DZNE), Bonn, 53175, Germany.
Protein Sci. 2016 May;25(5):1010-20. doi: 10.1002/pro.2911. Epub 2016 Mar 24.
Misfolding of the microtubule-associated protein Tau is a hallmark of Alzheimer disease and several other neurodegenerative disorders. Because of the dynamic nature of the Tau protein, little is known about the changes in Tau structure that occur during misfolding. Here we studied the structural consequences upon binding of the repeat domain of Tau, which plays a key role in pathogenic aggregation, to an aggregation enhancer. By combining NMR experiments with molecular simulations we show that binding of the aggregation enhancer polyglutamic acid remodels the conformational ensemble of Tau. Our study thus provides insight into an early event during misfolding of Tau.
微管相关蛋白Tau的错误折叠是阿尔茨海默病和其他几种神经退行性疾病的标志。由于Tau蛋白的动态性质，人们对错误折叠过程中Tau结构的变化知之甚少。在这里，我们研究了Tau的重复结构域（在致病性聚集中起关键作用）与聚集增强剂结合后的结构后果。通过将核磁共振实验与分子模拟相结合，我们表明聚集增强剂聚谷氨酸的结合重塑了Tau的构象集合。因此，我们的研究为Tau错误折叠过程中的早期事件提供了见解。
