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Title

Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers

AuthorsMannini, Benedetta; Roodveldt, Cintia ; Chiti, Fabrizio
KeywordsProtein homeostasis
Protein misfolding
Protein aggregates
Amyloid
Extracellular chaperones
Issue Date16-Jul-2012
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences 109(31): 12479-12484 (2012)
AbstractChaperones 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
DescriptionMannini, Benedetta et al.
Publisher version (URL)http://dx.doi.org/10.1073/pnas.1117799109
URIhttp://hdl.handle.net/10261/122471
DOI10.1073/pnas.1117799109
Identifiersissn: 0027-8424
e-issn: 1091-6490
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