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.

蛋白质聚集成淀粉样原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表征表明，二级成核途径通过在淀粉样原纤维表面吸收单体蛋白质来高度加速聚集。在这里，我们使用 NMR 和电子顺磁共振光谱来研究单体 α-突触核蛋白 (α-Syn) 与其纤维状形式的相互作用。我们证明 α-Syn 单体通过其带正电荷的 N 末端与纤维的带负电荷的柔性 C 末端瞬时相互作用。这些分子间相互作用减少了单体 α-Syn 中的分子内接触，产生部分塌陷的固有无序状态的 α-Syn 的进一步展开，同时可能增加可溶性 α-Syn 的局部浓度和原纤维表面上单个单体的排列。我们的数据表明，分子内展开对二次成核过程中 α-Syn 的聚集动力学有重要贡献。