Department for NMR based Structural Biology, Max Planck Institute for Biophysical Chemistry, D-37077, Goettingen, Germany.
Protein Sci. 2011 Feb;20(2):387-95. doi: 10.1002/pro.570.
The major component of neural inclusions that are the pathological hallmark of Parkinson's disease are amyloid fibrils of the protein α-synuclein (aS). Here we investigated if the disease-related mutation A30P not only modulates the kinetics of aS aggregation, but also alters the structure of amyloid fibrils. To this end we optimized the method of quenched hydrogen/deuterium exchange coupled to NMR spectroscopy and performed two-dimensional proton-detected high-resolution magic angle spinning experiments. The combined data indicate that the A30P mutation does not cause changes in the number, location and overall arrangement of β-strands in amyloid fibrils of aS. At the same time, several residues within the fibrillar core retain nano-second dynamics. We conclude that the increased pathogenicity related to the familial A30P mutation is unlikely to be caused by a mutation-induced change in the conformation of aS aggregates.
神经内含物的主要成分是帕金森病的病理学标志，是蛋白质α-突触核蛋白 (aS) 的淀粉样纤维。在这里，我们研究了疾病相关的 A30P 突变是否不仅调节了 aS 聚集的动力学，而且改变了淀粉样纤维的结构。为此，我们优化了与 NMR 光谱相结合的猝灭氢/氘交换方法，并进行了二维质子检测高分辨率魔角旋转实验。综合数据表明，A30P 突变不会导致 aS 纤维中β-折叠的数量、位置和整体排列发生变化。同时，纤维核心内的几个残基仍保留纳秒动力学。我们得出结论，与家族性 A30P 突变相关的致病性增加不太可能是由于突变诱导的 aS 聚集构象变化引起的。
