Wilkinson, M., Xu, Y., Thacker, D. et al. (5 more authors) (2023) Structural evolution of fibril polymorphs during amyloid assembly. Cell, 186 (26). 5798-5811.e26. ISSN 0092-8674
Abstract
Cryoelectron microscopy (cryo-EM) has provided unprecedented insights into amyloid fibril structures, including those associated with disease. However, these structures represent the endpoints of long assembly processes, and their relationship to fibrils formed early in assembly is unknown. Consequently, whether different fibril architectures, with potentially different pathological properties, form during assembly remains unknown. Here, we used cryo-EM to determine structures of amyloid fibrils at different times during in vitro fibrillation of a disease-related variant of human islet amyloid polypeptide (IAPP-S20G). Strikingly, the fibrils formed in the lag, growth, and plateau phases have different structures, with new forms appearing and others disappearing as fibrillation proceeds. A time course with wild-type hIAPP also shows fibrils changing with time, suggesting that this is a general property of IAPP amyloid assembly. The observation of transiently populated fibril structures has implications for understanding amyloid assembly mechanisms with potential new insights into amyloid progression in disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | amyloid; structural biology; protein aggregation; diabetes; kinetics; amyloid polymorphism; cryoEM; protein fibrils; protein structure |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Cryo EM, Image Processing (Leeds) |
Funding Information: | Funder Grant number MRC (Medical Research Council) MR/T011149/1 Wellcome Trust 108466/Z/15/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 04 Dec 2023 11:03 |
Last Modified: | 11 Jan 2024 16:38 |
Status: | Published |
Publisher: | Cell Press |
Identification Number: | 10.1016/j.cell.2023.11.025 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:206122 |