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| Título: | Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers |
Autor: | Mannini, Benedetta; Roodveldt, Cintia CSIC ORCID; Chiti, Fabrizio | Palabras clave: | Protein homeostasis Protein misfolding Protein aggregates Amyloid Extracellular chaperones |
Fecha de publicación: | 16-jul-2012 | Editor: | National Academy of Sciences (U.S.) | Citación: | Proceedings of the National Academy of Sciences 109(31): 12479-12484 (2012) | Resumen: | 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 | Descripción: | Mannini, Benedetta et al. | Versión del editor: | http://dx.doi.org/10.1073/pnas.1117799109 | URI: | http://hdl.handle.net/10261/122471 | DOI: | 10.1073/pnas.1117799109 | Identificadores: | issn: 0027-8424 e-issn: 1091-6490 |
| Aparece en las colecciones: | (CABIMER) Artículos |
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| protein oligomers.pdf | 9,44 MB | Adobe PDF |  Visualizar/Abrir |
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