Structural mapping of oligomeric intermediates in an amyloid assembly pathway
- University of Leeds, United Kingdom
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 DN6, a truncation variant of human β2-microglobulin (b2m) 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.
Data availability
Data are freely available at the University of Leeds Data Depository:https://doi.org/10.5518/329
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Structural Mapping of Oligomeric Intermediates InPDB file for dimer model.
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Structural Mapping of Oligomeric Intermediates InPDB file for hexamer model.
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Structural Mapping of Oligomeric Intermediates InRat cytotoxicity data.
Article and author information
Author details
Antonio N Calabrese
Funding
Wellcome Trust (089311/Z/09/Z)
- Theodoros K Karamanos
- Sheena E Radford
Wellcome Trust (204963)
- Sheena E Radford
Wellcome Trust (109154/Z/15/Z)
- Emma E Cawood
- Sheena E Radford
European Research Council (322408)
- Theodoros K Karamanos
- Matthew P Jackson
- Sheena E Radford
Biotechnology and Biological Sciences Research Council (BB/K000659/1)
- Antonio N Calabrese
- Sheena E Radford
Wellcome Trust (094232)
- Arnout P Kalverda
- Sheena E Radford
Biotechnology and Biological Sciences Research Council (BB/E012558/1)
- Sheena E Radford
Wellcome Trust (092896MA)
- Theodoros K Karamanos
- Sophia C Goodchild
- Sheena E Radford
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Karamanos et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structural mapping of oligomeric intermediates in an amyloid assembly pathway
eLife 8:e46574.
https://doi.org/10.7554/eLife.46574
