NR AUXI
AU Schwarzinger,S.; Horn,A.H.C.; Ziegler,J.; Sticht,H.
TI Rare large scale subdomain motions in prion protein can initiate aggregation
QU Journal of Biomolecular Structure and Dynamics 2006 Jun; 23(6): 581-90
PT journal article; review
AB The prion protein is thought to induce prion diseases by changing its conformation from the cellular form, PrPc, into the infectious Scrapie-form, PrPsc. 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 PrPc, 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 PrPc-conformers, which we named PrP(C*), contributes to the formation of pathogenic oligomeric species of the prion protein.
ZR 59
MH Animals; Humans; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; PrPc Proteins/*chemistry; PrPsc Proteins/*chemistry; Protein Conformation; Protein Folding; Protein Structure, Tertiary; Research Support, Non-U.S. Gov't
AD Lehrstuhl Biopolymere, Universität Bayreuth, Universitätsstrasse 30, 95447 Bayreuth, Germany. stephan.schwarzinger@uni-bayreuth.de
SP englisch
PO USA