Size and morphology of toxic oligomers of amyloidogenic proteins: a case study of human stefin B.
Identifieur interne : 002951 ( Main/Exploration ); précédent : 002950; suivant : 002952Size and morphology of toxic oligomers of amyloidogenic proteins: a case study of human stefin B.
Auteurs : Slavko Ceru [Slovénie] ; Sasa Jenko Kokalj ; Sabina Rabzelj ; Miha Skarabot ; Ion Gutierrez-Aguirre ; Natasa Kopitar-Jerala ; Gregor Anderluh ; Dusan Turk ; Vito Turk ; Eva ZerovnikSource :
- Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis [ 1744-2818 ] ; 2008.
Descripteurs français
- KwdFr :
- Amyloïde (), Amyloïde (ultrastructure), Cellules cancéreuses en culture, Chromatographie sur gel, Concentration en ions d'hydrogène, Cystatine B, Cystatines (), Cystatines (isolement et purification), Dimérisation, Double couche lipidique (), Double couche lipidique (métabolisme), Enchevêtrements neurofibrillaires (), Humains, Inhibiteurs de la cystéine protéinase (), Inhibiteurs de la cystéine protéinase (isolement et purification), Membrane cellulaire (métabolisme), Microscopie à force atomique, Neuroblastome (anatomopathologie), Neuroblastome (métabolisme), Survie cellulaire (physiologie).
- MESH :
- anatomopathologie : Neuroblastome.
- isolement et purification : Cystatines, Inhibiteurs de la cystéine protéinase.
- métabolisme : Double couche lipidique, Membrane cellulaire, Neuroblastome.
- physiologie : Survie cellulaire.
- ultrastructure : Amyloïde.
- Amyloïde, Cellules cancéreuses en culture, Chromatographie sur gel, Concentration en ions d'hydrogène, Cystatine B, Cystatines, Dimérisation, Double couche lipidique, Enchevêtrements neurofibrillaires, Humains, Inhibiteurs de la cystéine protéinase, Microscopie à force atomique.
English descriptors
- KwdEn :
- Amyloid (chemistry), Amyloid (ultrastructure), Cell Membrane (metabolism), Cell Survival (physiology), Chromatography, Gel, Cystatin B, Cystatins (chemistry), Cystatins (isolation & purification), Cysteine Proteinase Inhibitors (chemistry), Cysteine Proteinase Inhibitors (isolation & purification), Dimerization, Humans, Hydrogen-Ion Concentration, Lipid Bilayers (chemistry), Lipid Bilayers (metabolism), Microscopy, Atomic Force, Neuroblastoma (metabolism), Neuroblastoma (pathology), Neurofibrillary Tangles (chemistry), Tumor Cells, Cultured.
- MESH :
- chemical , chemistry : Amyloid, Cystatins, Cysteine Proteinase Inhibitors, Lipid Bilayers.
- chemical , isolation & purification : Cystatins, Cysteine Proteinase Inhibitors.
- chemical , metabolism : Lipid Bilayers.
- chemical , ultrastructure : Amyloid.
- chemistry : Neurofibrillary Tangles.
- metabolism : Cell Membrane, Neuroblastoma.
- pathology : Neuroblastoma.
- physiology : Cell Survival.
- Chromatography, Gel, Cystatin B, Dimerization, Humans, Hydrogen-Ion Concentration, Microscopy, Atomic Force, Tumor Cells, Cultured.
Abstract
Amyloid-induced toxicity is a well-known phenomenon but the molecular background remains unclear. One hypothesis relates toxicity to amyloid-membrane interactions, predicting that amyloid oligomers make pores into membranes. Therefore, the toxicity and membrane interaction of prefibrillar aggregates and individual oligomers of a non-pathological yet highly amyloidogenic protein human stefin B (cystatin B) was examined. By monitoring caspase-3 activity and by testing cell viability, we showed that the lag phase aggregates obtained at pH 5 and 3 were toxic to neuroblastoma cells. Of equal toxicity were the higher-order oligomers prepared at pH 7 by freeze-thaw cycles. The higher-order oligomers eluted on size-exclusion chromatography (SEC) as a broad peak comprising hexamers, octamers, 12- and 16-mers, well separated from monomers, dimers and tetramers. Only oligomers higher than the tetramers (Rh >3.5 nm) proved toxic, in contrast to dimers and tetramers. In accordance with data from SEC, dynamic light scattering and atomic force microscopy data indicate that the toxic oligomers have diameters larger than 4 nm. Critical pressure measurements showed that the toxic higher-order oligomers inserted more effectively into model lipid monolayers than dimers and tetramers. They also bound, similarly to prefibrillar aggregates, to the plasma membrane and became internalized. Taken together, our results confirm the importance of membrane interaction and perforation in the phenomenon of cytotoxicity.
DOI: 10.1080/13506120802193555
PubMed: 18925453
Affiliations:
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type="wicri:Area/Main/Exploration">002951</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Size and morphology of toxic oligomers of amyloidogenic proteins: a case study of human stefin B.</title><author><name sortKey="Ceru, Slavko" sort="Ceru, Slavko" uniqKey="Ceru S" first="Slavko" last="Ceru">Slavko Ceru</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Jozef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.</nlm:affiliation><country xml:lang="fr">Slovénie</country><wicri:regionArea>Department of Biochemistry, Jozef Stefan Institute, Jamova 39, 1000 Ljubljana</wicri:regionArea><wicri:noRegion>1000 Ljubljana</wicri:noRegion></affiliation></author><author><name sortKey="Kokalj, Sasa Jenko" sort="Kokalj, Sasa Jenko" uniqKey="Kokalj S" first="Sasa Jenko" last="Kokalj">Sasa Jenko Kokalj</name></author><author><name sortKey="Rabzelj, Sabina" sort="Rabzelj, Sabina" uniqKey="Rabzelj S" first="Sabina" last="Rabzelj">Sabina Rabzelj</name></author><author><name sortKey="Skarabot, Miha" sort="Skarabot, Miha" uniqKey="Skarabot M" first="Miha" last="Skarabot">Miha Skarabot</name></author><author><name sortKey="Gutierrez Aguirre, Ion" sort="Gutierrez Aguirre, Ion" uniqKey="Gutierrez Aguirre I" first="Ion" last="Gutierrez-Aguirre">Ion Gutierrez-Aguirre</name></author><author><name sortKey="Kopitar Jerala, Natasa" sort="Kopitar Jerala, Natasa" uniqKey="Kopitar Jerala N" first="Natasa" last="Kopitar-Jerala">Natasa Kopitar-Jerala</name></author><author><name sortKey="Anderluh, Gregor" sort="Anderluh, Gregor" uniqKey="Anderluh G" first="Gregor" last="Anderluh">Gregor Anderluh</name></author><author><name sortKey="Turk, Dusan" sort="Turk, Dusan" uniqKey="Turk D" first="Dusan" last="Turk">Dusan Turk</name></author><author><name sortKey="Turk, Vito" sort="Turk, Vito" uniqKey="Turk V" first="Vito" last="Turk">Vito Turk</name></author><author><name sortKey="Zerovnik, Eva" sort="Zerovnik, Eva" uniqKey="Zerovnik E" first="Eva" last="Zerovnik">Eva Zerovnik</name></author></analytic><series><title level="j">Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis</title><idno type="eISSN">1744-2818</idno><imprint><date when="2008" type="published">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amyloid (chemistry)</term><term>Amyloid (ultrastructure)</term><term>Cell Membrane (metabolism)</term><term>Cell Survival (physiology)</term><term>Chromatography, Gel</term><term>Cystatin B</term><term>Cystatins (chemistry)</term><term>Cystatins (isolation & purification)</term><term>Cysteine Proteinase Inhibitors (chemistry)</term><term>Cysteine Proteinase Inhibitors (isolation & purification)</term><term>Dimerization</term><term>Humans</term><term>Hydrogen-Ion Concentration</term><term>Lipid Bilayers (chemistry)</term><term>Lipid Bilayers (metabolism)</term><term>Microscopy, Atomic Force</term><term>Neuroblastoma (metabolism)</term><term>Neuroblastoma (pathology)</term><term>Neurofibrillary Tangles (chemistry)</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Amyloïde ()</term><term>Amyloïde (ultrastructure)</term><term>Cellules cancéreuses en culture</term><term>Chromatographie sur gel</term><term>Concentration en ions d'hydrogène</term><term>Cystatine B</term><term>Cystatines ()</term><term>Cystatines (isolement et purification)</term><term>Dimérisation</term><term>Double couche lipidique ()</term><term>Double couche lipidique (métabolisme)</term><term>Enchevêtrements neurofibrillaires ()</term><term>Humains</term><term>Inhibiteurs de la cystéine protéinase ()</term><term>Inhibiteurs de la cystéine protéinase (isolement et purification)</term><term>Membrane cellulaire (métabolisme)</term><term>Microscopie à force atomique</term><term>Neuroblastome 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xml:lang="fr"><term>Cystatines</term><term>Inhibiteurs de la cystéine protéinase</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cell Membrane</term><term>Neuroblastoma</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Double couche lipidique</term><term>Membrane cellulaire</term><term>Neuroblastome</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Neuroblastoma</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Survie cellulaire</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Cell Survival</term></keywords><keywords scheme="MESH" qualifier="ultrastructure" xml:lang="fr"><term>Amyloïde</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Chromatography, Gel</term><term>Cystatin B</term><term>Dimerization</term><term>Humans</term><term>Hydrogen-Ion Concentration</term><term>Microscopy, Atomic Force</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Amyloïde</term><term>Cellules cancéreuses en culture</term><term>Chromatographie sur gel</term><term>Concentration en ions d'hydrogène</term><term>Cystatine B</term><term>Cystatines</term><term>Dimérisation</term><term>Double couche lipidique</term><term>Enchevêtrements neurofibrillaires</term><term>Humains</term><term>Inhibiteurs de la cystéine protéinase</term><term>Microscopie à force atomique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Amyloid-induced toxicity is a well-known phenomenon but the molecular background remains unclear. One hypothesis relates toxicity to amyloid-membrane interactions, predicting that amyloid oligomers make pores into membranes. Therefore, the toxicity and membrane interaction of prefibrillar aggregates and individual oligomers of a non-pathological yet highly amyloidogenic protein human stefin B (cystatin B) was examined. By monitoring caspase-3 activity and by testing cell viability, we showed that the lag phase aggregates obtained at pH 5 and 3 were toxic to neuroblastoma cells. Of equal toxicity were the higher-order oligomers prepared at pH 7 by freeze-thaw cycles. The higher-order oligomers eluted on size-exclusion chromatography (SEC) as a broad peak comprising hexamers, octamers, 12- and 16-mers, well separated from monomers, dimers and tetramers. Only oligomers higher than the tetramers (Rh >3.5 nm) proved toxic, in contrast to dimers and tetramers. In accordance with data from SEC, dynamic light scattering and atomic force microscopy data indicate that the toxic oligomers have diameters larger than 4 nm. Critical pressure measurements showed that the toxic higher-order oligomers inserted more effectively into model lipid monolayers than dimers and tetramers. They also bound, similarly to prefibrillar aggregates, to the plasma membrane and became internalized. Taken together, our results confirm the importance of membrane interaction and perforation in the phenomenon of cytotoxicity.</div></front></TEI><affiliations><list><country><li>Slovénie</li></country></list><tree><noCountry><name sortKey="Anderluh, Gregor" sort="Anderluh, Gregor" uniqKey="Anderluh G" first="Gregor" last="Anderluh">Gregor Anderluh</name><name sortKey="Gutierrez Aguirre, Ion" sort="Gutierrez Aguirre, Ion" uniqKey="Gutierrez Aguirre I" first="Ion" last="Gutierrez-Aguirre">Ion Gutierrez-Aguirre</name><name sortKey="Kokalj, Sasa Jenko" sort="Kokalj, Sasa Jenko" uniqKey="Kokalj S" first="Sasa Jenko" last="Kokalj">Sasa Jenko Kokalj</name><name sortKey="Kopitar Jerala, Natasa" sort="Kopitar Jerala, Natasa" uniqKey="Kopitar Jerala N" first="Natasa" last="Kopitar-Jerala">Natasa Kopitar-Jerala</name><name sortKey="Rabzelj, Sabina" sort="Rabzelj, Sabina" uniqKey="Rabzelj S" first="Sabina" last="Rabzelj">Sabina Rabzelj</name><name sortKey="Skarabot, Miha" sort="Skarabot, Miha" uniqKey="Skarabot M" first="Miha" last="Skarabot">Miha Skarabot</name><name sortKey="Turk, Dusan" sort="Turk, Dusan" uniqKey="Turk D" first="Dusan" last="Turk">Dusan Turk</name><name sortKey="Turk, Vito" sort="Turk, Vito" uniqKey="Turk V" first="Vito" last="Turk">Vito Turk</name><name sortKey="Zerovnik, Eva" sort="Zerovnik, Eva" uniqKey="Zerovnik E" first="Eva" last="Zerovnik">Eva Zerovnik</name></noCountry><country name="Slovénie"><noRegion><name sortKey="Ceru, Slavko" sort="Ceru, Slavko" uniqKey="Ceru S" first="Slavko" last="Ceru">Slavko Ceru</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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