Copper and the structural biology of the prion protein

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.