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Manganese binding to the prion protein

Marcus W Brazier1, Paul Davies, Esmie Player

  • 1Department of Biology and Biochemistry and Chemistry, University of Bath, Bath BA2 7AY, UK.

The Journal of Biological Chemistry
|March 12, 2008
PubMed

Insights

Prion protein (PrP) binds manganese, similar to copper. Manganese binding alters PrP conformation, potentially triggering changes linked to prion disease.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Protein Chemistry

Background:

  • Prion protein (PrP) is known to bind copper.
  • Emerging evidence suggests PrP may also bind manganese.
  • Understanding metal-protein interactions is crucial for prion disease research.

Purpose of the Study:

  • To identify manganese binding sites in wild-type mouse PrP.
  • To characterize the biophysical and chemical consequences of manganese binding to PrP.
  • To investigate the potential role of manganese in PrP conformational changes.

Main Methods:

  • Isothermal titration calorimetry (ITC) to determine manganese binding affinities and sites.
  • Cyclic voltammetry to analyze the redox chemistry of metal-PrP complexes.
  • Conformational change assays to assess PrP aggregation.

Main Results:

  • PrP exhibits two manganese binding sites with significant affinity at physiological pH.
  • The primary manganese binding site involves His-95, overlapping with a known copper binding site.
  • Manganese binding alters PrP conformation, displaces copper, and changes the protein's redox properties.
  • Manganese-bound PrP catalyzes the aggregation of metal-free PrP, mimicking disease-associated changes.

Conclusions:

  • PrP binds manganese with affinities comparable to other manganese-binding proteins.
  • Manganese binding induces significant structural and functional alterations in PrP.
  • These manganese-induced changes in PrP may contribute to the pathogenesis of prion diseases.

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