Cinvestav, Stanford

Several neurodegenerative diseases, including transmissible spongiform encephalopathies diseases (TSEs), are characterized by the formation of proteic amyloid fibrils, where redox - active metals such as copper, iron and manganese also accumulate. [ 1 - 3 ] TSEs are associated to the conversion of the normal cellular form of prion protein (PrP^C) into the infectious scrapie isoform (PrP^Sc). [ 1 ] PrP^C has several binding sites for Cu at its N - terminal region. Human PrP^C contains four Cu binding sites at residues 60 - 91, [ 4 ] while two Cu binding sites are located at His96 and His111. [ 5, 6 ] The His111 site (His111) is located in a region that is key for the conversion of PrP^C to PrP^Sc; in fact, PrP(106 - 126) has similar properties to those of PrP^Sc, it is neurotoxic and generates hydrogen pero xide in the presence of Cu(II), reducing agents and oxygen. [ 7 ] Cu(II) binding to His111 is highly dependent on pH; two coordination modes (3N1O and 4N) are present at physiological pH. [ 8, 9 ]

In this work we study, both experimentally and theoretically, the coordination of Cu (I) to His111 in the human PrP(106 - 115) f ragment, evaluating the role of Met109 and Met112 in metal ion coordination . Our results indicate that the nature of the coordination shell of Cu(I) bound to PrP(106 - 115) is highly dependent on pH: at low pH it involves a NO2S coordination mode with the pa rticipation of Met109 and Met12, while at high pH a 2NOS coordination mode is favored, with a single Met residue bound to Cu(I). The participation of Met residues in the reduced form of Cu - PrP complexes is reflected in the reduction and re-oxidation proces ses. These results contribute to our understanding of the redox properties of this Cu binding site and provide insight into plausible mechanisms for copper transport by PrP^C .