NR ATRR
AU Stork,M.; Hirschberger,T.; Schropp,B.; Winklhofer,K.F.; Tatzelt,J.; Tavan,P.
TI Structural Instability of the Prion Protein upon M205S/R Mutations Revealed by Molecular Dynamics Simulations
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Structure of PrP and molecular determinants of infectivity STRCT-33
PT Konferenz-Poster
AB
The point mutations M205S and M205R have been demonstrated to interfere with the folding and maturation process of the cellular prion protein PrPc by preventing the complex posttranslational glycosylation and the attachment of the glycosylphosphatidylinositol (GPI) membrane anchor. These effects have been interpreted as consequences of mutation-induced structural changes in PrP, which were 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 PrPsc, which is the pathogenic isoform of PrPc in prion diseases, imply that helix 1 disappears during refolding of PrPc into PrPsc. Thus, they suggest that helix 1 is only marginally stable.
Based on molecular dynamics simulations of wild type and mutant PrPc in aqueous solution here we show that the native PrPc structure becomes severely 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 nearly complete decay of helix 1 confirming the suggested marginal stability of this helix.
AD M.Stork, T.Hirschberger, B.Schropp, P.Tavan, Theoretische Biophysik, Lehrstuhl für BioMolekulare Optik (BMO), Ludwig-Maximilians-Universität München, Oettingerstr. 67,80538 München, Germany; K.Winklhofer, J.Tatzelt, Department of cellular Biochemistry, Max-Planck-Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
SP englisch
PO Deutschland