Roles of methionine oxidation in E200K prion protein misfolding: Implications for the mechanism of pathogenesis in E200K linked familial Creutzfeldt-Jakob disease

Biochimica Et Biophysica Acta
Zonglin WangZheng Zhou

Abstract

Prion diseases are a group of neurodegenerative diseases caused by prion protein (PrP) conformational changes. More than 30 PRNP gene mutations have been associated with familial prion diseases. E200K-associated familial Creutzfeldt-Jakob disease (fCJD) is the most common inherited prion disease. One of the hallmarks of prion diseases is the accumulation of oxidative damage. The mechanism by which oxidative modification of methionine (Met) residues influence the E200K PrP misfolding remains unclear. Here, we examined the stability, structural change, oligomerization and proteinase K resistance of unoxidized/oxidized E200K PrP and Met-to-Leu mutants. We found that oxidation of surface-exposed Met109/112/129/134/154/166 residues significantly destabilized E200K PrP but had a limited impact on the protein's structure. The oxidation of Met213 was the initial step in the conformational conversion of E200K PrP and facilitated the further oxidation of Met205/206. The oxidation of Met213/205/206 led to the exposure of the inner hydrophobic core, disrupted the overall structure of E200K PrP and induced the formation of large soluble multimers at low pH. In addition, the aggregation behavior of oxidized E200K PrP at the cellular level wa...Continue Reading

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Citations

Mar 7, 2017·Journal of Inorganic Biochemistry·Gizella CsireCsilla Kállay
Jan 18, 2018·Journal of Neurochemistry·Michele Christine LandembergerVilma Regina Martins
Dec 30, 2017·Free Radical Research·Mark A RosenfeldAnna V Bychkova
Aug 4, 2020·Prion·John Bettinger, Sina Ghaemmaghami
Aug 12, 2019·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Daphne S CukiermanNicolás A Rey

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