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Article Dans Une Revue Journal of Biological Chemistry Année : 2015

The volumetric diversity of misfolded prion protein oligomers revealed by pressure dissociation

Résumé

Protein oligomerization has been associated with a wide range of diseases. High-pressure approaches offer a powerful tool for deciphering the underlying molecular mechanisms by revealing volume changes associated with the misfolding and assembly reactions. We applied high pressure to induce conformational changes in three distinct β-sheet-rich oligomers of the prion protein PrP, a protein characterized by a variety of infectious quaternary structures that can propagate stably and faithfully and cause diseases with specific phenotypic traits. We show that pressure induces dissociation of the oligomers and leads to a lower volume monomeric PrP state that refolds into the native conformation after pressure release. By measuring the different pressure- and temperature-sensitivity of the tested PrP oligomers, we demonstrate significantly different void volumes in their quaternary structure. In addition, by focusing on the kinetic and energetic behavior of the pressure-induced dissociation of one specific PrP oligomer, we reveal a large negative activation volume and an increase in both apparent activation enthalpy and entropy. This suggests a transition state ensemble that is less structured and significantly more hydrated than the oligomeric state. Finally, we found that site-specific fluorescent labeling allows monitoring the transient population of a kinetic intermediate in the dissociation reaction. Our results indicate that defects in atomic packing may deserve consideration as a new factor that influences differences between PrP assemblies and that could be relevant also for explaining the origin of prion strains.
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hal-01837415 , version 1 (27-05-2020)

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Joan Torrent, Reinhard Lange, Human Rezaei. The volumetric diversity of misfolded prion protein oligomers revealed by pressure dissociation. Journal of Biological Chemistry, 2015, 290 (33), pp.20417-20426. ⟨10.1074/jbc.M115.661710⟩. ⟨hal-01837415⟩
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