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

Autor:	Antonschmidt L; Department of NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany., Dervişoğlu R; Department of NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany., Sant V; Department of NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.; Department of Mechanical and Aerospace Engineering, University of California San Diego, San Diego, CA, USA., Tekwani Movellan K; Department of NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany., Mey I; Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Göttingen, Germany., Riedel D; Laboratory of Electron Microscopy, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany., Steinem C; Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Göttingen, Germany.; Biomolecular Chemistry Group, Max-Planck Institute for Dynamics and Self-Organization, Am Fassberg 17, 37077 Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Becker S; Department of NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany., Andreas LB; Department of NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany. land@nmr.mpibpc.mpg.de cigr@nmr.mpibpc.mpg.de., Griesinger C; Department of NMR-Based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany. land@nmr.mpibpc.mpg.de cigr@nmr.mpibpc.mpg.de.; Cluster of Excellence 'Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2021 May 14; Vol. 7 (20). Date of Electronic Publication: 2021 May 14 (Print Publication: 2021).
DOI:	10.1126/sciadv.abg2174
Abstrakt:	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. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze:	MEDLINE
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