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A Hairpin Motif in the Amyloid-& beta Peptide Is Important for Formation of Disease-Related Oligomers
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).ORCID iD: 0000-0003-3678-7100
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0003-2187-1537
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2023 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 145, no 33, p. 18340-18354Article in journal (Refereed) Published
Abstract [en]

The amyloid-& beta;(A & beta;) peptide is associated with the developmentof Alzheimer's disease and is known to form highly neurotoxicprefibrillar oligomeric aggregates, which are difficult to study dueto their transient, low-abundance, and heterogeneous nature. To obtainhigh-resolution information about oligomer structure and dynamicsas well as relative populations of assembly states, we here employa combination of native ion mobility mass spectrometry and moleculardynamics simulations. We find that the formation of A & beta; oligomersis dependent on the presence of a specific & beta;-hairpin motif inthe peptide sequence. Oligomers initially grow spherically but startto form extended linear aggregates at oligomeric states larger thanthose of the tetramer. The population of the extended oligomers couldbe notably increased by introducing an intramolecular disulfide bond,which prearranges the peptide in the hairpin conformation, therebypromoting oligomeric structures but preventing conversion into maturefibrils. Conversely, truncating one of the & beta;-strand-formingsegments of A & beta; decreased the hairpin propensity of the peptideand thus decreased the oligomer population, removed the formationof extended oligomers entirely, and decreased the aggregation propensityof the peptide. We thus propose that the observed extended oligomerstate is related to the formation of an antiparallel sheet state,which then nucleates into the amyloid state. These studies provideincreased mechanistic understanding of the earliest steps in A & beta;aggregation and suggest that inhibition of A & beta; folding into thehairpin conformation could be a viable strategy for reducing the amountof toxic oligomers.

Place, publisher, year, edition, pages
2023. Vol. 145, no 33, p. 18340-18354
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Chemical Sciences
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URN: urn:nbn:se:su:diva-221322DOI: 10.1021/jacs.3c03980ISI: 001044984100001PubMedID: 37555670Scopus ID: 2-s2.0-85168362360OAI: oai:DiVA.org:su-221322DiVA, id: diva2:1798532
Available from: 2023-09-19 Created: 2023-09-19 Last updated: 2023-09-19Bibliographically approved

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Rönnbäck, IsabelIlag, Leopold L.Gräslund, AstridÖsterlund, Nicklas

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Department of Biochemistry and BiophysicsDepartment of Materials and Environmental Chemistry (MMK)
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