Structural characterization of beta-sheeted oligomers formed on the pathway of oxidative prion protein aggregation in vitro.
Identifieur interne : 002B30 ( Main/Exploration ); précédent : 002B29; suivant : 002B31Structural characterization of beta-sheeted oligomers formed on the pathway of oxidative prion protein aggregation in vitro.
Auteurs : Lars Redecke [Allemagne] ; Martin Von Bergen ; Joachim Clos ; Peter V. Konarev ; Dimitri I. Svergun ; Ursula E A. Fittschen ; José A C. Broekaert ; Oliver Bruns ; Dessislava Georgieva ; Eckhard Mandelkow ; Nicolay Genov ; Christian BetzelSource :
- Journal of structural biology [ 1047-8477 ] ; 2007.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Polymers, PrPC Proteins.
- chemical , metabolism : PrPC Proteins.
- chemical , pharmacology : Copper.
- drug effects : Oxidative Stress.
- Amino Acid Sequence, Chemical Precipitation, Humans, Models, Chemical, Models, Molecular, Molecular Sequence Data, Protein Structure, Secondary.
Abstract
The pathology of transmissible spongiform encephalopathies (TSEs) is strongly associated with the structural conversion of the cellular prion protein (PrPC) into a misfolded isoform (PrPSc) that assembles into amyloid fibrils. Since increased levels of oxidative stress have been linked to prion diseases, we investigated the metal-induced oxidation of human PrP (90-231). A novel in vitro conversion assay based on aerobic incubation of PrP in the presence of elemental copper pellets at pH 5 was established, resulting in aggregation of highly beta-sheeted prion proteins. We show for the first time that two discrete oligomeric species of elongated shape, approx. 25 mers and 100 mers, are formed on the pathway of oxidative PrP aggregation in vitro, which are well characterized regarding shape and size using small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and electron microscopy (EM). Considering that small oligomers of highly similar size have recently been reported to show the highest specific infectivity within TSE-infected brain tissues of hamsters, the novel oligomers observed in this study are interesting candidates as agent causing neurodegenerative and/or self-propagating effects. Moreover, our results significantly strengthen the theory that oxidative stress might be an influence that leads to substantial structural conversions of PrP in vivo.
DOI: 10.1016/j.jsb.2006.06.013
PubMed: 17023178
Affiliations:
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<term>Chemical Precipitation</term>
<term>Copper (pharmacology)</term>
<term>Humans</term>
<term>Models, Chemical</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Oxidative Stress (drug effects)</term>
<term>Polymers (chemistry)</term>
<term>PrPC Proteins (chemistry)</term>
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<term>Modèles chimiques</term>
<term>Modèles moléculaires</term>
<term>Polymères ()</term>
<term>Protéines PrPC ()</term>
<term>Protéines PrPC (métabolisme)</term>
<term>Précipitation chimique</term>
<term>Stress oxydatif ()</term>
<term>Structure secondaire des protéines</term>
<term>Séquence d'acides aminés</term>
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<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Oxidative Stress</term>
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<term>Chemical Precipitation</term>
<term>Humans</term>
<term>Models, Chemical</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Protein Structure, Secondary</term>
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<term>Humains</term>
<term>Modèles chimiques</term>
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<term>Polymères</term>
<term>Protéines PrPC</term>
<term>Précipitation chimique</term>
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<front><div type="abstract" xml:lang="en">The pathology of transmissible spongiform encephalopathies (TSEs) is strongly associated with the structural conversion of the cellular prion protein (PrPC) into a misfolded isoform (PrPSc) that assembles into amyloid fibrils. Since increased levels of oxidative stress have been linked to prion diseases, we investigated the metal-induced oxidation of human PrP (90-231). A novel in vitro conversion assay based on aerobic incubation of PrP in the presence of elemental copper pellets at pH 5 was established, resulting in aggregation of highly beta-sheeted prion proteins. We show for the first time that two discrete oligomeric species of elongated shape, approx. 25 mers and 100 mers, are formed on the pathway of oxidative PrP aggregation in vitro, which are well characterized regarding shape and size using small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and electron microscopy (EM). Considering that small oligomers of highly similar size have recently been reported to show the highest specific infectivity within TSE-infected brain tissues of hamsters, the novel oligomers observed in this study are interesting candidates as agent causing neurodegenerative and/or self-propagating effects. Moreover, our results significantly strengthen the theory that oxidative stress might be an influence that leads to substantial structural conversions of PrP in vivo.</div>
</front>
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<name sortKey="Bruns, Oliver" sort="Bruns, Oliver" uniqKey="Bruns O" first="Oliver" last="Bruns">Oliver Bruns</name>
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<name sortKey="Georgieva, Dessislava" sort="Georgieva, Dessislava" uniqKey="Georgieva D" first="Dessislava" last="Georgieva">Dessislava Georgieva</name>
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<name sortKey="Svergun, Dimitri I" sort="Svergun, Dimitri I" uniqKey="Svergun D" first="Dimitri I" last="Svergun">Dimitri I. Svergun</name>
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<country name="Allemagne"><region name="Hambourg"><name sortKey="Redecke, Lars" sort="Redecke, Lars" uniqKey="Redecke L" first="Lars" last="Redecke">Lars Redecke</name>
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