Copper-ion interaction with the 106-113 domain of the prion protein: a solution-equilibria study on model peptides

Prion diseases are characterized by a structural modi. cation of the regular prion protein (PrPC) to its isoform, termed PrPSc (scrapie). Such a modi. cation involves the secondary and tertiary structure of the protein; the amino acidic sequence remains unchanged. PrPSc is almost insoluble in non-denaturing solvents, resistant to proteases and it loses its redox activity. PrPC is able to bind copper and other metal ions: these complexes have been suggested to play an important role in the protein refolding leading to PrPSc. It is well-known that at least one relatively strong copper-binding site is located in the PrP92-126 domain, where two His residues (96 and 111) are present. However, in the same domain, other amino acidic residues bear potentially donating atoms, i.e. Met, Asn and Lys residues. In order to shed light on the role of the side chains of such potentially tridentate amino acids on copper complexation, the polypeptide Ac-KTNMKHMA-NH2, corresponding to the PrP106-113 fragment, and some synthetic analogues have been investigated as ligands for the copper ion, by means of both thermodynamic and spectroscopic techniques. The pivotal role of imidazolic side chain of His in "anchoring" the metal ion has been confirmed. On the other hand, no clue was found on the participation of sulfur atom of Met or side amino-group of Lys residues to copper complex-formation.