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

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

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