A causative link between the structure of aberrant protein oligomers and their toxicity. Nat Chem Biol 6:140-147

Department of Biochemical Sciences, University of Florence, Florence, Italy.
Nature Chemical Biology (Impact Factor: 13). 02/2010; 6(2):140-7. DOI: 10.1038/nchembio.283
Source: PubMed


The aberrant assembly of peptides and proteins into fibrillar aggregates proceeds through oligomeric intermediates that are thought to be the primary pathogenic species in many protein deposition diseases. We describe two types of oligomers formed by the HypF-N protein that are morphologically and tinctorially similar, as detected with atomic force microscopy and thioflavin T assays, though one is benign when added to cell cultures whereas the other is toxic. Structural investigation at a residue-specific level using site-directed labeling with pyrene indicated differences in the packing of the hydrophobic interactions between adjacent protein molecules in the oligomers. The lower degree of hydrophobic packing was found to correlate with a higher ability to penetrate the cell membrane and cause an influx of Ca(2+) ions. Our findings suggest that structural flexibility and hydrophobic exposure are primary determinants of the ability of oligomeric assemblies to cause cellular dysfunction and its consequences, such as neurodegeneration.

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Available from: Silvia Campioni, Sep 08, 2014
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    • "The effect of metal ions on the dimerization of two Aβ peptides, the initial step in the amyloid cascade, is necessary to fully characterize the mechanism of how metal ions contribute to the pathogenesis of AD. AD is a neurodegenerative disease believed to be caused by the aggregation of the Aβ peptide into toxic oligomers456. These toxic oligomers can take the form of a variety of different morphologies including prefibrillar oligomers, amyloid derived diffusible ligands and annular protofibrils[7]. "
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    • "Accumulation of PC has been observed in several human diseases including Alzheimer's disease, diabetes, and arthritis [37]. Protein aggregates can be highly cytotoxic [38]. Carbonylated proteins that are not degraded may form potentially toxic aggregated species, and elevated levels of PC are linked to loss of cell viability [39]. "
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