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@ARTICLE{Elmallah:168223,
author = {Elmallah, Mohammed IY and Borgmeyer, Uwe and Betzel,
Christian and Redecke, Lars},
title = {{I}mpact of methionine oxidation as an initial event on the
pathway of human prion protein conversion},
journal = {Prion},
volume = {7},
number = {5},
issn = {1933-690X},
address = {Austin, Tex.},
publisher = {Landes Bioscience},
reportid = {DESY-2014-02424},
pages = {404 - 411},
year = {2013},
note = {© Landes Bioscience; Post referee fulltext in progress;
Embargo 12 months from publication},
abstract = {Prion diseases comprise a group of fatal neurodegenerative
disorders characterized by the autocatalytic conversion of
the cellular prion protein PrP(C) into the infectious
misfolded isoform PrP(Sc). Increasing evidence supports a
specific role of oxidative stress in the onset of
pathogenesis. Although the associated molecular mechanisms
remain to be elucidated in detail, several studies currently
suggest that methionine oxidation already detected in
misfolded PrP(Sc) destabilizes the native PrP fold as an
early event in the conversion pathway. To obtain more
insights about the specific impact of surface-exposed
methionine residues on the oxidative-induced conversion of
human PrP we designed, produced, and comparatively
investigated two new pseudosulfoxidation mutants of human
PrP 121-231 that comprises the well-folded C-terminal
domain. Applying circular dichroism spectroscopy and dynamic
light scattering techniques we showed that
pseudosulfoxidation of all surface exposed Met residues
formed a monomeric molten globule-like species with striking
similarities to misfolding intermediates recently reported
by other groups. However, individual pseudosulfoxidation at
the polymorphic M129 site did not significantly contribute
to the structural destabilization. Further metal-induced
oxidation of the partly unfolded pseudosulfoxidation mutant
resulted in the formation of an oligomeric state that shares
a comparable size and stability with PrP oligomers detected
after the application of different other triggers for
structural conversion, indicating a generic misfolding
pathway of PrP. The obtained results highlight the specific
importance of methionine oxidation at surface exposed
residues for PrP misfolding, strongly supporting the
hypothesis that increased oxidative stress could be one
causative event for sporadic prion diseases and other
neurodegenerative disorders.},
cin = {EMBL-User},
ddc = {570},
cid = {I:(DE-H253)EMBL-User-20120814},
pnm = {FS Beamline without reference (POF2-544)},
pid = {G:(DE-H253)POF2-No-Ref-20130405},
experiment = {EXP:(DE-H253)Unknown-BL-20150101},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000327383600007},
pubmed = {pmid:24121542},
doi = {10.4161/pri.26745},
url = {https://bib-pubdb1.desy.de/record/168223},
}