Can copper binding to the prion protein generate a misfolded form of the protein?

Abstract

The native prion protein (PrP) has a two domain structure, with a globular folded alpha-helical C-terminal domain and a flexible extended N-terminal region. The latter can selectively bind Cu(2+) via four His residues in the octarepeat (OR) region, as well as two sites (His96 and His111) outside this region. In the disease state, the folded C-terminal domain of PrP undergoes a conformational change, forming amorphous aggregates high in beta-sheet content. Cu(2+) bound to the ORs can be redox active and has been shown to induce cleavage within the OR region, a process requiring conserved Trp residues. Using computational modeling, we have observed that electron transfer from Trp residues to copper can be favorable. These models also reveal that an indole-based radical cation or Cu(+) can initiate reactions leading to protein backbone cleavage. We have also demonstrated, by molecular dynamics simulations, that Cu(2+) binding to the His96 and His111 residues in the remaining PrP N-terminal fragment can induce localized beta-sheet structure, allowing us to suggest a potential mechanism for the initiation of beta-sheet misfolding in the C-terminal domain by Cu(2+).

Metal Ion Physiopathology in Neurodegenerative Disorders

“…However, Waggoner et al (2000) reported that brain Cu levels and cuproenzyme activity in mice overexpressing PrP levels were unaffected when compared to controls. According to Pushie et al (2009) this could be explained by considering that Cu is not required for the propagation of PrP Sc , but only for its initial formation, and therefore, Cu is not expected to be enriched in prion plaques. Accordingly, the Cu chelator D-penicillamine seems to delay, and not to cure, the onset of the disease (Sigurdsson et al 2003).…”

Probing the coordination properties of glutathione with transition metal ions (Cr2+,Mn2+,Fe2+,Co2+, Ni2+,Cu2+,Zn2+,Cd2+,Hg2+) by density functional theory

“…The density functional method (DFT) is reliable and one of the most popular tools to describe metal-ligand interactions in biological systems, due to its excellent performance-to-cost ratio. Structural and electronic characterizations of the complexes formed by metal ions with amino acids were studied by the DFT method [38,39].The interaction between metal ions and organic molecules in the gas phase is an ideal environment from which complexation mechanisms can be obtained in the absence of any complicating solvent effects.…”

Copper (II) promotes the formation of soluble neurotoxic PrP oligomers in acidic environment

“…Copper ions are even preferentially coordinated by His96 and His111 in the unstructured amyloidogenic region of the prion protein between residues 90 and 120 [Jones et al, 2004; Osz, 2008; Viles et al, 2008; Di Natale et al, 2009]. Previous study suggested that PrP (90–231) might be more prone to chemical modification, and Cu 2+ binding to the His96 and His111 residues can induce localized β‐sheet structure [Nadal et al, 2007; Pushie et al, 2009]. The region of PrP located between 90 and 120 residues is also an important Cu 2+ binding site and strongly affects the structure of PrP, so we focused on the interaction of Cu 2+ and this truncated PrP (90–231).…”