Driving amyloid toxicity in a yeast model by structural changes: a molecular approach.
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.
Berthelot
Karine
K
Institut de Biochimie et Génétique Cellulaires, IBGC CNRS UMR 5095, Université Bordeaux 2 Victor Segalen, 1 rue Camille Saint Saëns, 33077 Bordeaux cedex, France.
Immel
Françoise
F
Géan
Julie
J
Lecomte
Sophie
S
Oda
Reiko
R
Kauffmann
Brice
B
Cullin
Christophe
C
D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity; D000686:Amyloidosis; D009154:Mutation; D017510:Protein Folding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction; D015003:Yeasts
D000682:Amyloid