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dc.contributor.author
Klose, Daniel
dc.contributor.author
Vemulapalli, Sahithya Phani Babu
dc.contributor.author
Richman, Michal
dc.contributor.author
Rudnick, Safra
dc.contributor.author
Aisha, Vered
dc.contributor.author
Abayev, Meital
dc.contributor.author
Chemerovski, Marina
dc.contributor.author
Shviro, Meital
dc.contributor.author
Zitoun, David
dc.contributor.author
Majer, Katharina
dc.contributor.author
Wili, Nino
dc.contributor.author
Goobes, Gil
dc.contributor.author
Griesinger, Christian
dc.contributor.author
Jeschke, Gunnar
dc.contributor.author
Rahimipour, Shai
dc.date.accessioned
2022-06-22T07:26:30Z
dc.date.available
2022-03-14T09:14:01Z
dc.date.available
2022-06-22T07:26:30Z
dc.date.issued
2022-03-21
dc.identifier.issn
1463-9084
dc.identifier.issn
1463-9076
dc.identifier.other
10.1039/d1cp05415e
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/536796
dc.description.abstract
In a wide spectrum of neurodegenerative diseases, self-assembly of pathogenic proteins to cytotoxic intermediates is accelerated by the presence of metal ions such as Cu2+. Only low concentrations of these early transient oligomeric intermediates are present in a mixture of species during fibril formation, and hence information on the extent of structuring of these oligomers is still largely unknown. Here, we investigate dimers as the first intermediates in the Cu2+-driven aggregation of a cyclic D,L-α-peptide architecture. The unique structural and functional properties of this model system recapitulate the self-assembling properties of amyloidogenic proteins including β-sheet conformation and cross-interaction with pathogenic amyloids. We show that a histidine-rich cyclic D,L-α-octapeptide binds Cu2+ with high affinity and selectivity to generate amyloid-like cross-β-sheet structures. By taking advantage of backbone amide methylation to arrest the self-assembly at the dimeric stage, we obtain structural information and characterize the degree of local order for the dimer. We found that, while catalytic amounts of Cu2+ promote aggregation of the peptide to fibrillar structures, higher concentrations dose-dependently reduce fibrillization and lead to formation of spherical particles, showing self-assembly to different polymorphs. For the initial self-assembly step to the dimers, we found that Cu2+ is coordinated on average by two histidines, similar to self-assembled peptides, indicating that a similar binding interface is perpetuated during Cu2+-driven oligomerization. The dimer itself is found in heterogeneous conformations that undergo dynamic exchange, leading to the formation of different polymorphs at the initial stage of the aggregation process.
en_US
dc.language.iso
en
en_US
dc.publisher
Royal Society of Chemistry
en_US
dc.title
Cu2+-Induced self-assembly and amyloid formation of a cyclic D,L-α-peptide: structure and function
en_US
dc.type
Journal Article
dc.date.published
2022-02-22
ethz.journal.title
Physical Chemistry Chemical Physics
ethz.journal.volume
24
en_US
ethz.journal.issue
11
en_US
ethz.journal.abbreviated
Phys. Chem. Chem. Phys.
ethz.pages.start
6699
en_US
ethz.pages.end
6715
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Cambridge
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02543 - Inst. f. Molekulare Physikalische Wiss. / Institute of Molecular Physical Science::03810 - Jeschke, Gunnar / Jeschke, Gunnar
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02543 - Inst. f. Molekulare Physikalische Wiss. / Institute of Molecular Physical Science::03810 - Jeschke, Gunnar / Jeschke, Gunnar
ethz.date.deposited
2022-03-14T09:14:31Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2022-06-22T07:26:46Z
ethz.rosetta.lastUpdated
2024-02-02T17:28:44Z
ethz.rosetta.versionExported
true
ethz.COinS
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