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J Mol Biol. 2011 Jul 15;410(3):369-82. doi: 10.1016/j.jmb.2011.05.013. Epub 2011 May 17.

Copper(II)-induced secondary structure changes and reduced folding stability of the prion protein.

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1
School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, UK.

Abstract

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 β-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 β-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.

PMID:
21619885
DOI:
10.1016/j.jmb.2011.05.013
[Indexed for MEDLINE]

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