A potential mechanism for Cu2+ reduction, beta-cleavage, and beta-sheet initiation within the N-terminal domain of the prion protein: insights from density functional theory and molecular dynamics calculations.

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Pushie MJ, Vogel HJ

J Toxicol Environ Health A. 2009;72(17-18):1040-59. doi: 10.1080/15287390903084389.

PubMed ID

19697239 [ View in PubMed

]

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 (Cu(2+)) 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 Cu(2+). At low concentrations of the metal ion or at low pH, one Cu(2+) may be bound by multiple His residues of the four octarepeats. This complex is known to be redox active, while none of the other Cu(2+)-bound complexes are. Using density functional theory and molecular dynamics calculations data demonstrated how this form of the protein could reduce Cu(2+), 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 beta-cleavage of the prion protein chain at any of the Gly residues around position 90. Protein fragments of lengths similar to those arising from beta-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 Cu(2+) 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 beta-sheet structures that might associate in the same fashion with additional prion proteins.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Copper	Alternative prion protein	Protein	Humans	Unknown	Not Available	Details