Direct three-dimensional visualization of membrane disruption by amyloid fibrils
Milanesi, Lilia and Sheynis, T. and Xue, W.-F. and Orlova, Elena and Hellewell, A.L. and Jelinek, R. and Hewitt, E.W. and Radford, S.E. and Saibil, Helen R. (2012) Direct three-dimensional visualization of membrane disruption by amyloid fibrils. Proceedings of the National Academy of Sciences of the United States of America 109 (50), pp. 20455-20460. ISSN 0027-8424.
Abstract
Protein misfolding and aggregation cause serious degenerative conditions such as Alzheimer’s, Parkinson, and prion diseases. Damage to membranes is thought to be one of the mechanisms underlying cellular toxicity of a range of amyloid assemblies. Previous studies have indicated that amyloid fibrils can cause membrane leakage and elicit cellular damage, and these effects are enhanced by fragmentation of the fibrils. Here we report direct 3D visualization of membrane damage by specific interactions of a lipid bilayer with amyloid-like fibrils formed in vitro from β2-microglobulin (β2m). Using cryoelectron tomography, we demonstrate that fragmented β2m amyloid fibrils interact strongly with liposomes and cause distortions to the membranes. The normally spherical liposomes form pointed teardrop-like shapes with the fibril ends seen in proximity to the pointed regions on the membranes. Moreover, the tomograms indicated that the fibrils extract lipid from the membranes at these points of distortion by removal or blebbing of the outer membrane leaflet. Tiny (15–25 nm) vesicles, presumably formed from the extracted lipids, were observed to be decorating the fibrils. The findings highlight a potential role of fibrils, and particularly fibril ends, in amyloid pathology, and report a previously undescribed class of lipid–protein interactions in membrane remodelling.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Administrator |
| Date Deposited: | 09 Jan 2013 11:11 |
| Last Modified: | 02 Aug 2023 17:01 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/5916 |
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