Karamanos, TK orcid.org/0000-0003-2297-540X, Jackson, MP orcid.org/0000-0002-4416-3499, Calabrese, AN orcid.org/0000-0003-2437-7761 et al. (6 more authors) (2019) Structural mapping of oligomeric intermediates in an amyloid assembly pathway. eLife, 8. e46574. ISSN 2050-084X
Abstract
Transient oligomers are commonly formed in the early stages of amyloid assembly. Determining the structure(s) of these species and defining their role(s) in assembly is key to devising new routes to control disease. Here, using a combination of chemical kinetics, NMR spectroscopy and other biophysical methods, we identify and structurally characterize the oligomers required for amyloid assembly of the protein ΔN6, a truncation variant of human β2-microglobulin (β2m) found in amyloid deposits in the joints of patients with dialysis-related amyloidosis. The results reveal an assembly pathway which is initiated by the formation of head-to-head non-toxic dimers and hexamers en route to amyloid fibrils. Comparison with inhibitory dimers shows that precise subunit organization determines amyloid assembly, while dynamics in the C-terminal strand hint to the initiation of cross-β structure formation. The results provide a detailed structural view of early amyloid assembly involving structured species that are not cytotoxic.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © Karamanos et al. This is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (https://creativecommons.org/licenses/by/4.0/) |
Keywords: | E. coli; molecular biophysics; structural biology |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Biomolecular Mass Spectroscopy (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > NMR (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 01 Oct 2019 15:27 |
Last Modified: | 17 Dec 2024 14:46 |
Status: | Published |
Publisher: | eLife Sciences Publications |
Identification Number: | 10.7554/elife.46574 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:151478 |
Downloads
Filename: elife-46574-v2.pdf
Licence: CC-BY 4.0
Filename: elife-46574-figures-v2.pdf
Licence: CC-BY 4.0