Journal
SCIENCE ADVANCES
Volume 7, Issue 20, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg2174
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Funding
- project A04 of the SFB 803
- Emmy Noether program [AN1316/1-1]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [EXC 2067/1-390729940]
- Max Planck Society
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Recent advances in the structural biology of disease-relevant alpha-synuclein fibrils have shed light on a variety of structures, while investigations into the aggregation process have identified key time points for the isolation of prefibrillar and early fibrillar intermediates, revealing a segmental folding process.
Recent advances in the structural biology of disease-relevant.-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.-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.-synuclein fibril filament, revealing a segmental folding process. We identify distinct membrane-binding domains in.-synuclein aggregates, and the combined data are used to present a comprehensive mechanism of the folding of.-synuclein on lipid membranes.
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