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Ion mobility–mass spectrometry reveals a conformational conversion from random assembly to β-sheet in amyloid fibril formation

Nature Chemistry volume 3, pages 172–177 (2011)Cite this article

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Abstract

Amyloid cascades that lead to peptide β-sheet fibrils and plaques are central to many important diseases. Recently, intermediate assemblies of these cascades were identified as the toxic agents that interact with cellular machinery. The location and cause of the transformation from a natively unstructured assembly to the β-sheet oligomers found in all fibrils is important in understanding disease onset and the development of therapeutic agents. Largely, research on this early oligomeric region was unsuccessful because all the traditional techniques measure only the average oligomer properties of the ensemble. We utilized ion-mobility methods to deduce the peptide self-assembly mechanism and examined a series of amyloid-forming peptides clipped from larger peptides or proteins associated with disease. We provide unambiguous evidence for structural transitions in each of these fibril-forming peptide systems and establish the potential of this method for the development of therapeutic agents and drug evaluation.

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Figure 1: Proposed processes during the soluble stage of peptide self-assembly in amyloid formation.
Figure 2: Peptide aggregation observed by IMS-MS for the peptides YGGFL and VEALYL.
Figure 3: AFM imaging for the peptides YGGFL and VEALYL.
Figure 4: Measured collision cross-sections as a function of the oligomer number n for YGGFL, NNQQNY, VEALYL and SSTNVG.
Figure 5: Proposed self-assembly pathways of YGGFL, NNQQNY, VEALYL and SSTNVG.

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Acknowledgements

This research was supported by the National Science Foundation and the National Institutes of Health. A prototype Synapt instrument was provided by the Waters Corporation. C.B. thanks the Alexander von Humboldt Foundation for a Feodor Lynen Fellowship. The authors thank J. O'Dea for obtaining the AFM images. We thank R. Gleiter and D.B. Werz for useful discussions.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, Santa Barbara, 93106–9510, California, USA

    Christian Bleiholder, Nicholas F. Dupuis, Thomas Wyttenbach & Michael T. Bowers

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  1. Christian Bleiholder
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Contributions

C.B., N.F.D. and T.W. made the measurements and C.B. and M.T.B. designed the study and co-wrote the paper.

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Correspondence to Michael T. Bowers.

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Bleiholder, C., Dupuis, N., Wyttenbach, T. et al. Ion mobility–mass spectrometry reveals a conformational conversion from random assembly to β-sheet in amyloid fibril formation. Nature Chem 3, 172–177 (2011). https://doi.org/10.1038/nchem.945

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