Copper(II)-Induced Secondary Structure Changes and Reduced Folding Stability of the Prion Protein

N D Younan, M Klewpatinond, Paul Davies, A V Ruban, David R Brown, J H Viles

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The cellular isoform of the prion protein PrP(C) is a Cu(2+)-binding cell surface glycoprotein that, when misfolded, is responsible for a range of transmissible spongiform encephalopathies. As changes in PrP(C) conformation are intimately linked with disease pathogenesis, the effect of Cu(2+) ions on the structure and stability of the protein has been investigated. Urea unfolding studies indicate that Cu(2+) ions destabilise the native fold of PrP(C). The midpoint of the unfolding transition is reduced by 0.73 +/- 0.07 M urea in the presence of 1 mol equiv of Cu(2+). This equates to an appreciable difference in free energy of unfolding (2.02 +/- 0.05 kJ mol(-1) at the midpoint of unfolding). We relate Cu(2+)-induced changes in secondary structure for full-length PrP(23-231) to smaller Cu(2+) binding fragments. In particular, Cu(2+)-induced structural changes can directly be attributed to Cu(2+) binding to the octarepeat region of PrP(C). Furthermore, a beta-sheet-like transition that is observed when Cu ions are bound to the amyloidogenic fragment of PrP (residues 90-126) is due only to local Cu(2+) coordination to the individual binding sites centred at His95 and His110. Cu(2+) binding does not directly generate a beta-sheet conformation within PrP(C); however, Cu(2+) ions do destabilise the native fold of PrP(C) and may make the transition to a misfolded state more favourable.
Original languageEnglish
Pages (from-to)369-382
Number of pages14
JournalJournal of Molecular Biology
Issue number3
Publication statusPublished - 15 Jul 2011


  • urea
  • unfolding
  • circular dichroism
  • PrP
  • Cu(2+)


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