title: 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+).
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, AB, Canada.
authors.forename: M Jake
authors.initials: MJ
authors.lastname: Pushie
authors.forename: Arvi
authors.initials: A
authors.lastname: Rauk
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jirik
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Vogel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry
chemical_list: D007211:Indoles; D011328:Prions; D017665:Hydroxyl Radical; D003300:Copper; D014364:Tryptophan