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The effect of β2-α2 loop mutation on amyloidogenic properties of the prion protein

Arpana Dutta1, Shugui Chen, Witold K Surewicz

  • 1Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.

FEBS Letters
|July 30, 2013
PubMed

Insights

A specific mutation in mouse prion protein (moPrP) increases its tendency to form amyloid fibrils, leading to prion disease. This enhanced amyloid formation stems from the protein's sequence, not loop rigidity.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Molecular Biology

Background:

  • Prion diseases are linked to misfolded prion proteins (PrP).
  • Specific mutations in mouse prion protein (moPrP) can induce prion diseases.
  • The elk-like S170N/N174T mutation in moPrP causes prion disease in transgenic mice, associated with increased β2-α2 loop rigidity.

Purpose of the Study:

  • To investigate the biophysical effects of the S170N/N174T mutation on moPrP.
  • To determine the underlying mechanism driving the increased prion disease propensity.

Main Methods:

  • Characterization of thermodynamic stability of wild-type and mutant moPrP.
  • Assessment of amyloid fibril formation propensity under various conditions.
  • Analysis of the role of loop rigidity versus amino acid sequence in amyloidogenesis.

Main Results:

  • Mutant moPrP (S170N/N174T) exhibits a significantly higher propensity for amyloid fibril formation compared to wild-type moPrP.
  • Thermodynamic stabilities of wild-type and mutant moPrP are similar.
  • Increased amyloid formation by mutant moPrP persists even under fully denaturing conditions.

Conclusions:

  • The S170N/N174T mutation enhances moPrP's conversion propensity not due to increased loop rigidity.
  • The mutation's amino acid sequence within the loop region possesses greater inherent amyloidogenic potential.
  • This intrinsic amyloidogenic potential of the mutant sequence is the primary driver of prion disease development.
Keywords:
AmyloidGuHClPrPPrion diseasePrion proteinProtein structureThTguanidine hydrochloridemoPrPmouse prion proteinprion proteinthioflavin Twild typewt

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