Rare large scale subdomain motions in prion protein can initiate aggregation

Journal of Biomolecular Structure & Dynamics
Stephan SchwarzingerHeinrich Sticht

Abstract

The prion protein is thought to induce prion diseases by changing its conformation from the cellular form, PrP(C), into the infectious Scrapie-form, PrP(Sc). Little is known about the structural and dynamical features of this conformational change. We here introduce a novel concept that involves rare large scale motions between the subdomains beta1-alpha1-beta2 and alpha2-alpha3 in the carboxy-terminal, globular part of PrP. The interface between these two subdomains carries most pathogenic mutations known to be associated with prion diseases. Based on computational simulations as well as experimental results we propose that such a large scale motion subsequently destabilizes large parts of the cellular conformer PrP(C), thus, rendering it prone to structural rearrangements, including aggregation of now partially unfolded parts of the PrP sequence. We hypothesize that such large scale motions occur as a rare event even under equilibrium conditions and that the interaction of such partially destabilized PrP(C)-conformers, which we named PrP(C*), contributes to the formation of pathogenic oligomeric species of the prion protein.

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Citations

Jan 6, 2010·European Biophysics Journal : EBJ·Martin LingenheilPaul Tavan
Sep 9, 2011·The Journal of Biological Chemistry·Abhay Kumar ThakurChintalagiri Mohan Rao
Jan 10, 2012·Biophysical Journal·Carlo CamilloniAlfonso De Simone
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Aug 11, 2012·Journal of Biomolecular Structure & Dynamics·Alfonso De SimoneLuciana Esposito
Apr 18, 2009·The Journal of Physical Chemistry. B·Yassmine Chebaro, Philippe Derreumaux
Sep 17, 2010·The Journal of Physical Chemistry. B·Sara R R CamposAntónio M Baptista
Mar 20, 2015·Chemical Reviews·Jessica Nasica-LabouzePhilippe Derreumaux

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