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

MPS-Authors
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Antonschmidt,  L.
Department of NMR Based Structural Biology, MPI for Biophysical Chemistry, Max Planck Society;

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Dervisoglu,  R.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Tekwani Movellan,  K.
Research Group of Solid State NMR Spectroscopy-2, MPI for Biophysical Chemistry, Max Planck Society;

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Riedel,  D.
Facility for Electron Microscopy, MPI for biophysical chemistry, Max Planck Society;

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Becker,  S.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Andreas,  L. B.
Research Group of Solid State NMR Spectroscopy-2, MPI for Biophysical Chemistry, Max Planck Society;

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Griesinger,  C.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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3348040.pdf
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Citation

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.


Cite as: http://hdl.handle.net/21.11116/0000-0009-689A-5
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.