Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor

Abstract

Amyloid formation has been implicated in the pathology of over 20 human diseases, but the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid–inhibitor complexes. We use isotope labelling and two-dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin (the peptide responsible for islet amyloid formation in type 2 diabetes) with a known inhibitor (rat amylin). Based on its sequence, rat amylin should block formation of the C-terminal β-sheet, but at 8 h after mixing, rat amylin blocks the N-terminal β-sheet instead. At 24 h after mixing, rat amylin blocks neither β-sheet and forms its own β-sheet, most probably on the outside of the human fibrils. This is striking, because rat amylin is natively disordered and not previously known to form amyloid β-sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes. Molecular inhibitors of amyloid formation could help combat Alzheimer's disease, type 2 diabetes, and other major human diseases. Here, two-dimensional infrared spectroscopy and residue-specific isotope labelling are used to obtain detailed structural information on amyloid-inhibitor complexes. The unexpected behaviour observed helps to explain the moderate activity of the inhibitor studied.

Cite this article

Middleton, C., Marek, P., Cao, P. et al. Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor. Nature Chem 4, 355–360 (2012). https://doi.org/10.1038/nchem.1293

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