Oxidation of methionine residues in the prion protein by hydrogen peroxide.
Reaction of H(2)O(2) with the recombinant SHa(29-231) prion protein resulted in rapid oxidation of multiple methionine residues. Susceptibility to oxidation of individual residues, assessed by mass spectrometry after digestion with CNBr and lysC, was in general a function of solvent exposure. Met 109 and Met 112, situated in the highly flexible amino terminus, and key residues of the toxic peptide PrP (106-126), showed the greatest susceptibility. Met 129, a residue located in a polymorphic position in human PrP and modulating risk of prion disease, was also easily oxidized, as was Met 134. The structural effect of H(2)O(2)-induced methionine oxidation on PrP was studied by CD spectroscopy. As opposed to copper catalyzed oxidation, which results in extensive aggregation of PrP, this reaction led only to a modest increase in beta-sheet structure. The high number of solvent exposed methionine residues in PrP suggests their possible role as protective endogenous antioxidants.
Requena
Jesús R
JR
Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. requenaj@usc.es
Dimitrova
Mariana N
MN
Legname
Giuseppe
G
Teijeira
Susana
S
Prusiner
Stanley B
SB
Levine
Rodney L
RL
D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D006861:Hydrogen Peroxide / Q000737:chemistry*; D008647:Mesocricetus; D008715:Methionine / Q000737:chemistry*; D046912:Multiprotein Complexes / Q000737:chemistry; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
D046912:Multiprotein Complexes; D010446:Peptide Fragments; D011328:Prions; D011994:Recombinant Proteins; D008715:Methionine; D006861:Hydrogen Peroxide