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Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers
Faculty of Science - Papers (Archive)
  • Benedetta Mannini, University of Florence
  • Roberta Cascella, University of Florence
  • Mariagiola Zampagni, University of Florence
  • Maria van Waarde-Verhagen, University of Groningen
  • Sarah Meehan, University of Cambridge
  • Cintia Roodveldt, Universidad De Sevilla
  • Silvia Campioni, Swiss Federal Institute Of Technology
  • Matilde Boninsegna, University of Florence
  • Amanda Penco, University Of Genoa
  • Annalisa Relini, University Of Genoa
  • Harm H Kampinga, University of Groningen
  • Christopher M Dobson, University of Cambridge
  • Mark R Wilson, University of Wollongong
  • Cristina Cecchi, University of Florence
  • Fabrizio Chiti, University of Florence
RIS ID
66391
Publication Date
1-1-2012
Publication Details

Mannini, B., Cascella, R., Zampagni, M., van Waarde-Verhagen, M., Meehan, S., Roodveldt, C., Campioni, S., Boninsegna, M., Penco, A., Relini, A., Kampinga, H. H., Dobson, C. M., Wilson, M. R., Cecchi, C. & Chiti, F. (2012). Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers. Proceedings of the National Academy of Sciences of the United States of America, 109 (31), 12479-12484.

Abstract
Chaperones are the primary regulators of the proteostasis network and are known to facilitate protein folding, inhibit protein aggregation, and promote disaggregation and clearance of misfolded aggregates inside cells. We have tested the effects of five chaperones on the toxicity of misfolded oligomers preformed from three different proteins added extracellularly to cultured cells. All the chaperones were found to decrease oligomer toxicity significantly, even at very low chaperone/protein molar ratios, provided that they were added extracellularly rather than being overexpressed in the cytosol. Infrared spectroscopy and site-directed labeling experiments using pyrene ruled out structural reorganizations within the discrete oligomers. Rather, confocal microscopy, SDS-PAGE, and intrinsic fluorescence measurements indicated tight binding between oligomers and chaperones. Moreover, atomic force microscopy imaging indicated that larger assemblies of oligomers are formed in the presence of the chaperones. This suggests that the chaperones bind to the oligomers and promote their assembly into larger species, with consequent shielding of the reactive surfaces and a decrease in their diffusional mobility. Overall, the data indicate a generic ability of chaperones to neutralize extracellular misfolded oligomers efficiently and reveal that further assembly of protein oligomers into larger species can be an effective strategy to neutralize such extracellular species.
Citation Information
Benedetta Mannini, Roberta Cascella, Mariagiola Zampagni, Maria van Waarde-Verhagen, et al.. "Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers" (2012) p. 12479 - 12484
Available at: http://works.bepress.com/mark_wilson/30/