Structural instability of the prion protein upon M205S/R mutations revealed by molecular dynamics simulations

Biophysical Journal
Thomas HirschbergerPaul Tavan

Abstract

The point mutations M205S and M205R have been demonstrated to severely disturb the folding and maturation process of the cellular prion protein (PrP(C)). These disturbances have been interpreted as consequences of mutation-induced structural changes in PrP, which are suggested to involve helix 1 and its attachment to helix 3, because the mutated residue M205 of helix 3 is located at the interface of these two helices. Furthermore, current models of the prion protein scrapie (PrP(Sc)), which is the pathogenic isoform of PrP(C) in prion diseases, imply that helix 1 disappears during refolding of PrP(C) into PrP(Sc). Based on molecular-dynamics simulations of wild-type and mutant PrP(C) in aqueous solution, we show here that the native PrP(C) structure becomes strongly distorted within a few nanoseconds, once the point mutations M205S and M205R have been applied. In the case of M205R, this distortion is characterized by a motion of helix 1 away from the hydrophobic core into the aqueous environment and a subsequent structural decay. Together with experimental evidence on model peptides, this decay suggests that the hydrophobic attachment of helix 1 to helix 3 at M205 is required for its correct folding into its stable native struc...Continue Reading

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Citations

Jan 6, 2010·European Biophysics Journal : EBJ·Martin LingenheilPaul Tavan
May 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Christina WolschnerNediljko Budisa
Oct 6, 2010·Journal of Biomolecular Structure & Dynamics·Linghao Zhong
Jul 14, 2010·PLoS Pathogens·Tamar CanelloRuth Gabizon
Nov 5, 2014·Journal of Molecular Modeling·Parameswaran SaravananSanjukta Patra
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Oct 26, 2006·Chemical Biology & Drug Design·Luisa RongaFilomena Rossi
Jan 1, 2008·Bioinformatics and Biology Insights·Kanaka Durga KedarisettiLukasz Kurgan
Aug 4, 2020·Prion·John Bettinger, Sina Ghaemmaghami
Aug 1, 2008·Journal of Chemical Theory and Computation·M LingenheilP Tavan
Feb 24, 2007·Biochemistry·Mari L DeMarco, Valerie Daggett

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