Department of Chemistry and Applied Biosciences, Laboratory of Physical Chemistry, ETH Zurich, 8093 Zurich, Switzerland.
Department of Chemistry and Applied Biosciences, Laboratory of Physical Chemistry, ETH Zurich, 8093 Zurich, Switzerland;
Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). doi: 10.1073/pnas.2012171118.
Protein aggregation into amyloid fibrils is associated with multiple neurodegenerative diseases, including Parkinson's disease. Kinetic data and biophysical characterization have shown that the secondary nucleation pathway highly accelerates aggregation via the absorption of monomeric protein on the surface of amyloid fibrils. Here, we used NMR and electron paramagnetic resonance spectroscopy to investigate the interaction of monomeric α-synuclein (α-Syn) with its fibrillar form. We demonstrate that α-Syn monomers interact transiently via their positively charged N terminus with the negatively charged flexible C-terminal ends of the fibrils. These intermolecular interactions reduce intramolecular contacts in monomeric α-Syn, yielding further unfolding of the partially collapsed intrinsically disordered states of α-Syn along with a possible increase in the local concentration of soluble α-Syn and alignment of individual monomers on the fibril surface. Our data indicate that intramolecular unfolding critically contributes to the aggregation kinetics of α-Syn during secondary nucleation.
蛋白质聚集形成淀粉样纤维与多种神经退行性疾病有关，包括帕金森病。动力学数据和生物物理特性表明，次级成核途径通过将单体蛋白吸收到淀粉样纤维表面，极大地加速了聚集。在这里，我们使用 NMR 和电子顺磁共振波谱研究了单体α-突触核蛋白（α-Syn）与纤维形式的相互作用。我们证明α-Syn 单体通过其带正电荷的 N 端与纤维的带负电荷的柔性 C 端瞬时相互作用。这些分子间相互作用减少了单体α-Syn 中的分子内接触，导致α-Syn 的部分折叠的固有无序状态进一步展开，以及可溶性α-Syn 的局部浓度增加，并使单体在纤维表面上排列。我们的数据表明，分子内展开对次级成核过程中α-Syn 的聚集动力学至关重要。
