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Protein Misfolding Cyclic Amplification of Prions
10:12

Protein Misfolding Cyclic Amplification of Prions

Published on: November 7, 2012

Instability of familial spongiform encephalopathy-related prion mutants

Yasuko Watanabe1, Wakako Hiraoka, Yuhei Shimoyama

  • 1Laboratory of Radiation Biology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.

Biochemical and Biophysical Research Communications
|December 8, 2007
PubMed

Insights

The D177N mutation destabilizes the S2 region in mouse prion protein (moPrP(C)), impacting hereditary prion disease mechanisms. This study reveals how salt bridge disruption affects protein structure and disease formation.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Neuroscience

Background:

  • Prion diseases are linked to misfolded prion proteins (PrPSc).
  • The cellular prion protein (PrPC) undergoes conformational changes.
  • Understanding these changes is crucial for hereditary prion diseases.

Purpose of the Study:

  • To investigate the impact of the D177N mutation on the conformational stability of the S2 region in mouse prion protein (moPrP(C)).
  • To elucidate the role of salt bridges and protonation in S2 region stability.
  • To understand the structural basis of pathogenic PrPSc formation in hereditary prion disease.

Main Methods:

  • Site-directed spin labeling electron spin resonance (SDSL-ESR) technique.
  • Analysis of ESR spectra at varying pH levels (7.5 and 4.0).
  • Comparison of mutant (D177N) and wild-type (WT) moPrP(C) spectra.

Main Results:

  • The D177N mutation resulted in a narrower ESR spectrum compared to WT at pH 7.5.
  • The ESR spectrum of D177N remained unchanged upon decreasing pH to 4.0, indicating increased instability.
  • Disruption of the D177-R163 salt bridge and protonation of H176 were strongly associated with S2 region instability.

Conclusions:

  • The D177N mutation destabilizes the S2 region of moPrP(C) by disrupting the D177-R163 salt bridge.
  • Protonation of H176 is critical for S2 region stability.
  • These findings provide insights into the mechanism of PrPSc formation in hereditary prion diseases.

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