Structural insights into α-synuclein monomer-fibril interactions

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 a-synuclein (alpha-Syn) with its fibrillar form. We demonstrate that alpha-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 alpha-Syn, yielding further unfolding of the partially collapsed intrinsically disordered states of alpha-Syn along with a possible increase in the local concentration of soluble alpha-Syn and alignment of individual monomers on the fibril surface. Our data indicate that intramolecular unfolding critically contributes to the aggregation kinetics of alpha-Syn during secondary nucleation.

Automated summary

This study investigated the interaction between monomeric alpha-Syn and its fibrillar form using NMR and electron paramagnetic resonance spectroscopy, revealing that intermolecular interactions reduce intramolecular contacts in monomeric alpha-Syn, leading to further unfolding of its intrinsically disordered states and critically contributing to the aggregation kinetics of alpha-Syn during secondary nucleation.