Abstract
The N-terminal region of the native human prion protein encompasses four highly conserved octarepeats that each contain a single His, Pro, Gln, and Trp residue as well as several Gly residues. At neutral pH these repeats are capable of individually binding copper (Cu2+) ions, involving the His side chain and the backbone amide of the Gly residues. In addition, the two His residues at positions 96 and 111 are also capable of binding Cu2+. At low concentrations of the metal ion or at low pH, one Cu2+ may be bound by multiple His residues of the four octarepeats. This complex is known to be redox active, while none of the other Cu2+-bound complexes are. Using density functional theory and molecular dynamics calculations data demonstrated how this form of the protein could reduce Cu2+, through a process involving electron transfer from the Trp side chain. The reduced Cu gives rise to reactive oxygen species (ROS), which can lead to β‐cleavage of the prion protein chain at any of the Gly residues around position 90. Protein fragments of lengths similar to those arising from β-cleavage are predominantly found in both healthy and Creutzfeldt–Jakob disease (CJD)-affected brains. Models of Cu binding to the His96 and His111 residues also indicate that different modes of Cu2+ binding result in formation of stable beta-hairpin structures in this region of the protein. It is postulated that through interactions with the C-terminal part of the protein these hairpins may initiate misfolding and yield more stable β-sheet structures that might associate in the same fashion with additional prion proteins.
Acknowledgements
M. J. Pushie was supported by an Alberta Ingenuity studentship and H. J. Vogel holds a Scientist award from the Alberta Heritage Foundation for Medical Research. This research has been enabled by the use of WestGrid computing resources, which are funded in part by the Canada Foundation for Innovation, Alberta Innovation and Science, BC Advanced Education, and participating research institutions. We thank Dr. A. Rauk at the University of Calgary for insightful discussions.