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dc.contributor.authorCanello, Tamar
dc.contributor.authorFrid, Kati
dc.contributor.authorGabizon, Ronen
dc.contributor.authorLisa, Silvia
dc.contributor.authorFriedler, Assaf
dc.contributor.authorMoskovitz, Jackob
dc.contributor.authorGasset, María
dc.contributor.authorGabizon, Ruth
dc.date.accessioned2014-03-17T21:29:01Z
dc.date.available2014-03-17T21:29:01Z
dc.date.issued2010-07-01
dc.identifier.citationCanello, 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
dc.identifier.urihttp://hdl.handle.net/1808/13186
dc.description.abstractWhile 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.
dc.description.sponsorshipThis work has been supported by grants from the Israeli Science foundation and The Israeli Ministry of Health (RG) as well as grants BFU2009-07971 from the Ministerio de Ciencia e Innovación (MG) and PI101209 from the Fundación Cien (MG).
dc.publisherPublic Library of Science
dc.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.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAntibodies
dc.subjectCreutzfeldt-Jakob disease
dc.subjectMethionine
dc.subjectMutation
dc.subjectOxidation
dc.subjectPrion diseases
dc.subjectProteases
dc.subjectVeterinary prion diseases
dc.titleOxidation of Helix-3 Methionines Precedes the Formation of PK Resistant PrPSc
dc.typeArticle
kusw.kuauthorMoskovitz, Jackob
kusw.kudepartmentDepartment of Pharmacology and Toxicology
kusw.oastatusfullparticipation
dc.identifier.doi10.1371/journal.ppat.1000977
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


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©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.
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.