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Molecular recycling within amyloid fibrils

Abstract

Amyloid fibrils are thread-like protein aggregates with a core region formed from repetitive arrays of β-sheets oriented parallel to the fibril axis1,2. Such structures were first recognized in clinical disorders1,3, but more recently have also been linked to a variety of non-pathogenic phenomena ranging from the transfer of genetic information to synaptic changes associated with memory4,5,6,7. The observation that many proteins can convert into similar structures in vitro has suggested that this ability is a generic feature of polypeptide chains1,8. Here we have probed the nature of the amyloid structure by monitoring hydrogen/deuterium exchange in fibrils formed from an SH3 domain9,10,11,12 using a combination of nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry. The results reveal that under the conditions used in this study, exchange is dominated by a mechanism of dissociation and re-association that results in the recycling of molecules within the fibril population. This insight into the dynamic nature of amyloid fibrils, and the ability to determine the parameters that define this behaviour, have important implications for the design of therapeutic strategies directed against amyloid disease.

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Figure 1: H/D exchange of PI(3)K-SH3 amyloid fibrils monitored by NMR spectroscopy.
Figure 2: H/D exchange of PI(3)K-SH3 amyloid fibrils analysed by ESI-MS.
Figure 3: Electron micrographs and H/D exchange data for fibril suspensions subjected to different processing strategies.
Figure 4: The molecular recycling model.

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Acknowledgements

N.C. acknowledges receipt of a Marie Curie Fellowship and a Marie Curie Reintegration Grant from the EC. G.L.C. acknowledges support from the Walters-Kundert Trust and the EPSRC. D.R.H. acknowledges receipt of an HFSP Fellowship. The research of C.V.R. is supported in part by the Royal Society, and that of C.M.D. and J.Z. by Programme Grants from the Wellcome Trust and the Leverhulme Trust.

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Correspondence to Christopher M. Dobson.

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This contains the Supplementary Methods, Supplementary Discussion, Supplementary Figures and Supplementary Tables. It also contains additional references. (DOC 277 kb)

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Carulla, N., Caddy, G., Hall, D. et al. Molecular recycling within amyloid fibrils. Nature 436, 554–558 (2005). https://doi.org/10.1038/nature03986

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