Urbanek, A., Garland, E., Prescott, E. et al. (11 more authors) (2025) Molecular determinants of protein pathogenicity at the single-aggregate level. Advanced Science, 12 (9). 2410229. ISSN 2198-3844
Abstract
Determining the structure-function relationships of protein aggregates is a fundamental challenge in biology. These aggregates, whether formed in vitro, within cells, or in living organisms, present significant heterogeneity in their molecular features such as size, structure, and composition, making it difficult to determine how their structure influences their functions. Interpreting how these molecular features translate into functional roles is crucial for understanding cellular homeostasis and the pathogenesis of various debilitating diseases like Alzheimer's and Parkinson's. In this study, we introduce a bottom-up approach to explore how variations in protein aggregates’ size, composition, post-translational modifications and point mutations profoundly influence their biological functions. Applying this method to Alzheimer's and Parkinson's associated proteins, we uncover the mechanism of novel disease-relevant pathways and demonstrate how subtle alterations in composition and morphology can shift the balance between healthy and pathological states. Our findings provide deeper insights into the molecular basis of protein’s functions at the single-aggregate level, enhancing our knowledge of their roles in health and disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/ |
Keywords: | Protein aggregation; Neurodegenerative disease; Single-molecule imaging; Structure-function relationship |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Funding Information: | Funder Grant number ACADEMY OF MEDICAL SCIENCES SBF006\1038 UK RESEARCH AND INNOVATION MR/V023861/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 03 Jan 2025 12:40 |
Last Modified: | 12 Mar 2025 12:31 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/advs.202410229 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:220996 |