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

Thomas Hirschberger1, Martina Stork, Bernhard Schropp

  • 1Theoretische Biophysik, Lehrstuhl für BioMolekulare Optik, Ludwig-Maximilians-Universität, Oettingenstrasse 67, D-80538 Munich, Germany.

Biophysical Journal
|March 4, 2006
PubMed

Insights

Point mutations in cellular prion protein (PrP(C)) disrupt its structure and maturation. The M205R mutation causes helix 1 to detach, leading to structural decay and highlighting the importance of hydrophobic interactions for PrP(C) folding.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Neuroscience

Background:

  • Cellular prion protein (PrP(C)) is crucial for normal neurological function.
  • Misfolding of PrP(C) into pathogenic PrP(Sc) underlies prion diseases.
  • Point mutations M205S and M205R are known to disrupt PrP(C) folding and maturation.

Purpose of the Study:

  • To investigate the structural consequences of M205S and M205R mutations on PrP(C) folding.
  • To elucidate the role of helix 1 and its interaction with helix 3 in PrP(C) stability.
  • To understand the molecular mechanisms underlying PrP(C) misfolding relevant to prion diseases.

Main Methods:

  • Molecular-dynamics simulations of wild-type and mutant PrP(C) in aqueous solution.
  • Analysis of structural changes, including helix movement and hydrophobic core integrity.
  • Integration of experimental evidence from model peptides.

Main Results:

  • PrP(C) structure is significantly distorted within nanoseconds upon M205S and M205R mutations.
  • The M205R mutation induces a notable displacement of helix 1 from the hydrophobic core.
  • This displacement leads to subsequent structural decay, indicating a loss of native PrP(C) conformation.

Conclusions:

  • The hydrophobic attachment of helix 1 to helix 3 at residue M205 is essential for the stable native structure of PrP(C).
  • Disturbances in this interaction promote PrP(C) misfolding, potentially contributing to prion disease pathogenesis.
  • These findings provide molecular insights into the structural basis of prion proteinopathies.

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