Insights into the molecular mechanism of amyloid filament formation: Segmental folding of α-synuclein on lipid membranes
Leif Antonschmidt, Rıza Dervişoğlu, Vrinda Sant, Kumar Tekwani Movellan, Ingo Mey, Dietmar Riedel, Claudia Steinem, Stefan Becker, Loren B. Andreas, Christian Griesinger
Abstract
Recent advances in the structural biology of disease-relevant α-synuclein fibrils have revealed a variety of structures, yet little is known about the process of fibril aggregate formation. Characterization of intermediate species that form during aggregation is crucial; however, this has proven very challenging because of their transient nature, heterogeneity, and low population. Here, we investigate the aggregation of α-synuclein bound to negatively charged phospholipid small unilamellar vesicles. Through a combination of kinetic and structural studies, we identify key time points in the aggregation process that enable targeted isolation of prefibrillar and early fibrillar intermediates. By using solid-state nuclear magnetic resonance, we show the gradual buildup of structural features in an α-synuclein fibril filament, revealing a segmental folding process. We identify distinct membrane-binding domains in α-synuclein aggregates, and the combined data are used to present a comprehensive mechanism of the folding of α-synuclein on lipid membranes.