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FASEB J. 2009 Jul;23(7):2254-63. doi: 10.1096/fj.08-125724. Epub 2009 Feb 19.

Driving amyloid toxicity in a yeast model by structural changes: a molecular approach.

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  • 1Institut de Biochimie et Génétique Cellulaires, IBGC CNRS UMR 5095, Université Bordeaux 2 Victor Segalen, 1 rue Camille Saint Saëns, 33077 Bordeaux cedex, France.


The amyloid aggregation pathway is a multistep process, and many in vitro studies have highlighted the role of particular intermediates in the cellular toxicity of various amyloid diseases. In a previous study, we generated a yeast toxic mutant (M8) of the harmless model amyloid protein Het-s(218-289). In this study, we compared the aggregation characteristics of the wild-type (WT) and the toxic mutant at the molecular level. Both proteins formed fibrillar amyloid aggregates but with different dye-binding properties and X-ray diffraction patterns. The toxic amyloid formed very unusual short (80 nm) unbranched fibers visible on transmission electron microscopy. Fourier transform infrared spectroscopy demonstrated that M8 beta-sheets were essentially organized into a mixed parallel and antiparallel structure, whereas the WT protein displayed a predominantly parallel organization. Cellular toxicity may therefore be related to assembly of the toxic amyloid in a new aggregation pathway.

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