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"Structural Instability of the Prion Protein upon M205S/R Mutations Revealed by Molecular Dynamics Simulations" Thomas Hirschberger, Martina Stork, Bernhard Schropp, Konstanze F. Winklhofer, Jörg Tatzelt, and Paul TavanBiophys. J. 90, 3908-3918 (2006). 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 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 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 here we show 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 structure. BMO authors (in alphabetic order): Thomas Hirschberger Bernhard Schropp Martina Stork Paul Tavan Assoziierte Projekte: Structural Stability of the Cellular Prion Protein PrPC studied by MD-Simulations Computation of structure, electrostatics, and conformational dynamics of PrPC induced by binding of Cu(II) |
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Letzte Änderung: 2016-09-14 13:34
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