NR AWNL
AU Schwarzinger,S.; Horn,A.H.C.; Ziegler,J.; Sticht,H.
TI Aggregation initiation in prion protein by rare subdomain motions
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions S-19
PT Konferenz-Poster
AB The prion protein is thought to be the causative agens in transmissible spongiform encephalopathies, such as Creutzfeldt-Jakob disease (CJD) in man or bovine spongiform encephalopathy (BSE) in cattle. It is assumed that the disease is induced by a change of the prion protein conformation from the cellular form, PrPc, into the infectious Scrapie-form, PrPsc. Little is known about the structural and dynamical features of this pathogenic conformational change. Here we present a novel concept involving rare large scale motions between the subdomains ß1-alpha1-ß2 and alpha2-alpha3 in the carboxyterminal, globular part of PrPc. The interface between these two subdomains carries a significant number of destabilizing, pathogenic mutations known to be associated with prion diseases. Based on computational simulations and experimental results from our own as well as from published research we propose that such a large scale motion subsequently destabilizes large parts of the cellular conformer PrPc thus rendering it susceptible to structural rearrangements, including aggregation of now partially unfolded parts of the PrP sequence. We propose that such large scale subdomainmotions occur as a rare event even under equilibrium conditions and that the interaction of such partially destabilized PrPc-conformers, which we name PrPc*, contributes to the formation of infectious oligomeric species of the prion protein.
AD S. Schwarzinger, J. Ziegler: Department of Biopolymers, University of Bayreuth, Bayreuth, Germany; A.H.C. Horn, H. Sticht: Department of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-University, Erlangen, Germany. E-mail: stephan.schwarzinger@uni-bayreuth.de
SP englisch
PO Italien