Oxidation of Helix-3 Methionines Precedes the Formation of PK Resistant PrPSc

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Issue Date
2010-07-01Author
Canello, Tamar
Frid, Kati
Gabizon, Ronen
Lisa, Silvia
Friedler, Assaf
Moskovitz, Jackob
Gasset, María
Gabizon, Ruth
Publisher
Public Library of Science
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
©2010 Canello et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Show full item recordAbstract
While elucidating the peculiar epitope of the α-PrP mAb IPC2, we found that PrPSc exhibits the sulfoxidation of residue M213 as a covalent signature. Subsequent computational analysis predicted that the presence of sulfoxide groups at both Met residues 206 and 213 destabilize the α-fold, suggesting oxidation may facilitate the conversion of PrPC into PrPSc. To further study the effect of oxidation on prion formation, we generated pAbs to linear PrP peptides encompassing the Helix-3 region, as opposed to the non-linear complexed epitope of IPC2. We now show that pAbs, whose epitopes comprise Met residues, readily detected PrPC, but could not recognize most PrPSc bands unless they were vigorously reduced. Next, we showed that the α-Met pAbs did not recognize newly formed PrPSc, as is the case for the PK resistant PrP present in lines of prion infected cells. In addition, these reagents did not detect intermediate forms such as PK sensitive and partially aggregated PrPs present in infected brains. Finally, we show that PrP molecules harboring the pathogenic mutation E200K, which is linked to the most common form of familial CJD, may be spontaneously oxidized. We conclude that the oxidation of methionine residues in Helix-3 represents an early and important event in the conversion of PrPC to PrPSc. We believe that further investigation into the mechanism and role of PrP oxidation will be central in finally elucidating the mechanism by which a normal cell protein converts into a pathogenic entity that causes fatal brain degeneration.
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- Pharmacy Scholarly Works [293]
Citation
Canello, T., Frid, K., Gabizon, R., Lisa, S., Friedler, A., Moskovitz, J., … Gabizon, R. (2010). Oxidation of Helix-3 Methionines Precedes the Formation of PK Resistant PrPSc. PLoS Pathog, 6(7). http://dx.doi.org/10.1371/journal.ppat.1000977
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Except where otherwise noted, this item's license is described as: ©2010 Canello et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.