PrP (prion-related protein) is a cell-surface Cu2+-binding glycoprotein which, when misfolded, is responsible for a number of transmissible spongiform encephalopathies. The co-ordination geometry, stoichiometry and affinity of Cu2+ for PrP are the subject of much debate. In the present paper, we review the recent progress we have made in these areas. As many as six Cu2+ ions bind to PrP with submicromolar affinity. Initially, two Cu2+ ions bind to full-length PrP in the amyloidogenic region, between the octarepeats and the structured domain, at His95 and His110. Only subsequent Cu2+ ions bind to single histidine residues within the octarepeat region. Competitive chelators have been used to determine the affinity of the first molar equivalent of Cu2+ bound to full-length PrP; this approach places the affinity in the nanomolar range. The affinity and number of Cu2+-binding sites support the suggestion that PrP could act as an antioxidant by binding potentially harmful Cu2+ ions and sacrificially quenching of free radicals generated as a result of copper redox cycling. Finally, the effect of Cu2+ on the prion structure and misassembly into oligomers and fibres is discussed.

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