Methionine oxidation perturbs the structural core of the prion protein and suggests a generic misfolding pathway

N.D. Younan, R.C. Nadal, P. Davies, David R. Brown, J.H. Viles

Research output: Contribution to journalArticlepeer-review

41 Citations (SciVal)


Oxidative stress and misfolding of the prion protein (PrPC) are fundamental to prion diseases. We have therefore probed the effect of oxidation on the structure and stability of PrPC. Urea unfolding studies indicate that H2O2 oxidation reduces the thermodynamic stability of PrPC by as much as 9 kJ/mol. 1H-15N NMR studies indicate methionine oxidation perturbs key hydrophobic residues on one face of helix-C as follows: Met-205, Val-209, and Met-212 together with residues Val-160 and Tyr-156. These hydrophobic residues pack together and form the structured core of the protein, stabilizing its ternary structure. Copper-catalyzed oxidation of PrPC causes a more significant alteration of the structure, generating a monomeric molten globule species that retains its native helical content. Further copper-catalyzed oxidation promotes extended β-strand structures that lack a cooperative fold. This transition from the helical molten globule to β-conformation has striking similarities to a misfolding intermediate generated at low pH. PrP may therefore share a generic misfolding pathway to amyloid fibers, irrespective of the conditions promoting misfolding. Our observations support the hypothesis that oxidation of PrP destabilizes the native fold of PrPC, facilitating the transition to PrPSc. This study gives a structural and thermodynamic explanation for the high levels of oxidized methionine in scrapie isolates.
Original languageEnglish
Pages (from-to)28263-28275
Number of pages13
JournalJournal of Biological Chemistry
Issue number34
Early online date30 May 2012
Publication statusPublished - 17 Aug 2012


Dive into the research topics of 'Methionine oxidation perturbs the structural core of the prion protein and suggests a generic misfolding pathway'. Together they form a unique fingerprint.

Cite this