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  Insights into the molecular mechanism of amyloid filament formation: Segmental folding of α-synuclein on lipid membranes

Antonschmidt, L., Dervisoglu, R., Sant, V., Tekwani Movellan, K., Mey, I., Riedel, D., et al. (2021). Insights into the molecular mechanism of amyloid filament formation: Segmental folding of α-synuclein on lipid membranes. Science Advances, 7(20): eabg2174. doi:10.1126/sciadv.abg2174.

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Antonschmidt, L.1, Author              
Dervisoglu, R.2, Author              
Sant, V., Author              
Tekwani Movellan, K.3, Author              
Mey, I., Author
Riedel, D.4, Author              
Steinem, C., Author
Becker, S.2, Author              
Andreas, L. B.3, Author              
Griesinger, C.2, Author              
Affiliations:
1Department of NMR Based Structural Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_578567              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
3Research Group of Solid State NMR Spectroscopy-2, MPI for Biophysical Chemistry, Max Planck Society, ou_2396693              
4Facility for Electron Microscopy, MPI for biophysical chemistry, Max Planck Society, ou_578615              

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 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.

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Language(s): eng - English
 Dates: 2021-05-14
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1126/sciadv.abg2174
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Title: Science Advances
Source Genre: Journal
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Pages: 12 Volume / Issue: 7 (20) Sequence Number: eabg2174 Start / End Page: - Identifier: -