Article

A causative link between the structure of aberrant protein oligomers and their toxicity.

Department of Biochemical Sciences, University of Florence, Florence, Italy.
Nature Chemical Biology (Impact Factor: 13.22). 02/2010; 6(2):140-7. DOI: 10.1038/nchembio.283
Source: PubMed

ABSTRACT 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.

1 Follower
 · 
179 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aberrant assembly of proteins into fibrillar aggregates is accused to be the primary cause of pathogenesis of neurodegenerative diseases. But the structural determinants of protein fibrils that are responsible for cell dysfunction are not yet clear. In the current study, cell culture, spectroscopic techniques as well as theoretical and structural investigations were used to determine the ability of different fibrillar aggregates to impair cell viability. We evaluated two types of amyloid fibrils that efficiently impair cell viability when added to cell culture. Theoretical and structural investigations indicated differences in the hydrophobic characteristics of protein molecules in the fibrils, so that our findings suggest that surface hydrophobicity may be considered as a main determinant of fibrillar assemblies to cause cellular dysfunction and its consequences such as neurodegeneration. Also, the main objective of the present study was to discuss the potential role of peroxidase activity of “heme-amyloid fibril” complex in neurodegenerative disorders onset/progression using the protein-based experimental models. The results of the present study also suggest that oxidative stress may be involved in neurodegenerative cell toxicity via several independent (mechanistic) routes. The data on origin of amyloid-mediated cell dysfunction may help us t
  • Source
    Non-fibrillar Amyloidogenic Protein Assemblies—Common Cytotoxins Underlying Degenerative Diseases, Edited by Farid Rahimi, Gal Bitan, 01/2012: chapter Overview of fibrillar and oligomeric assemblies of amyloidogenic proteins: pages 1-36; Springer., ISBN: 9789400727731
  • Source
    Frontiers in Neurology 12/2014; 5:276. DOI:10.3389/fneur.2014.00276

Full-text

Download
16 Downloads
Available from
Sep 8, 2014