The amyloidogenic region of the human prion protein contains a high affinity (Met)(2)(His)(2) Cu(I) binding site.
The prion protein (PrP(c)) is a cuproprotein implicated in a number of human neurodegenerative diseases. Although many physiological functions have been ascribed to PrP, its potential to act as a neuronal antioxidant, based in part on its copper binding ability, is controversial and unresolved. A number of studies have shown that copper bound to PrP(c) is not redox silent, and recent data shows that the Cu(II) sites at histidines 96 and 111 display reversible electrochemistry. Reversible electrochemistry implies redox cycling whilst the metal remains bound and with the absence of permanent oxidation or reduction of the protein. Despite this indirect evidence of Cu(I) binding to PrP, the nature of the Cu(I) binding site/s is unclear, although previous extended X-ray absorption fine structure (EXAFS) data has implicated methionines in the Cu(I) binding site. Using spectroscopic techniques we find that the PrP region encompassing histidines 96 and 111 can bind a Cu(I) ion in a site comprising His 96, His 111, Met 109 and Met 112. The four-coordinate (His)(2)(Met)(2) Cu(I) site has a K(d)=10(-15)-10(-12)M indicative of high affinity. Mutation of histidine residues reduces the Cu(I) affinity. Although alluding to the fact the PrP could act in a direct superoxide dismutase-like fashion, the Cu(I)-PrP(91-124) site and affinity is comparable to that observed for bacterial periplasmic Cu(I) transporters.
Badrick
Alison C
AC
Centre for Metals in Biology, The University of Queensland, St. Lucia, Australia.
Jones
Christopher E
CE
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D001665:Binding Sites; D003300:Copper / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008715:Methionine / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D011485:Protein Binding; D013053:Spectrophotometry
D000682:Amyloid; D009842:Oligopeptides; D011328:Prions; D006639:Histidine; D003300:Copper; D008715:Methionine