Copper and the structural biology of the prion protein.
PrP (prion-related protein) is a cell-surface Cu(2+)-binding glycoprotein which, when misfolded, is responsible for a number of transmissible spongiform encephalopathies. The co-ordination geometry, stoichiometry and affinity of Cu(2+) 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 Cu(2+) ions bind to PrP with submicromolar affinity. Initially, two Cu(2+) ions bind to full-length PrP in the amyloidogenic region, between the octarepeats and the structured domain, at His(95) and His(110). Only subsequent Cu(2+) 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 Cu(2+) bound to full-length PrP; this approach places the affinity in the nanomolar range. The affinity and number of Cu(2+)-binding sites support the suggestion that PrP could act as an antioxidant by binding potentially harmful Cu(2+) ions and sacrificially quenching of free radicals generated as a result of copper redox cycling. Finally, the effect of Cu(2+) on the prion structure and misassembly into oligomers and fibres is discussed.
Viles
John H
JH
School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London, UK. j.viles@qmul.ac.uk
Klewpatinond
Mark
M
Nadal
Rebecca C
RC
D000818:Animals; D003300:Copper / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding
D016166:Free Radical Scavengers; D010446:Peptide Fragments; D011328:Prions; D003300:Copper