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The Kinetics of Amyloid Fibrillar Aggregation of Uperin 3.5 Is Directed by the Peptide's Secondary Structure

John, Torsten; Dealey, Tiara J A; Gray, Nicholas P.; Patil, Nitin A; Hossain, Mohammed A.; Abel, Bernd; Carver, John; Hong, Yuning; Martin, Lisandra

Description

Many peptides aggregate into insoluble β-sheet rich amyloid fibrils. Some of these aggregation processes are linked to age-related diseases, such as Alzheimer’s disease and type 2 diabetes. Here, we show that the secondary structure of the peptide uperin 3.5 directs the kinetics and mechanism of amyloid fibrillar aggregation. Uperin 3.5 variants were investigated using thioflavin T fluorescence assays, circular dichroism spectroscopy, and structure prediction methods. Our results suggest that...[Show more]

dc.contributor.authorJohn, Torsten
dc.contributor.authorDealey, Tiara J A
dc.contributor.authorGray, Nicholas P.
dc.contributor.authorPatil, Nitin A
dc.contributor.authorHossain, Mohammed A.
dc.contributor.authorAbel, Bernd
dc.contributor.authorCarver, John
dc.contributor.authorHong, Yuning
dc.contributor.authorMartin, Lisandra
dc.date.accessioned2020-05-07T01:18:37Z
dc.identifier.issn0006-2960
dc.identifier.urihttp://hdl.handle.net/1885/203844
dc.description.abstractMany peptides aggregate into insoluble β-sheet rich amyloid fibrils. Some of these aggregation processes are linked to age-related diseases, such as Alzheimer’s disease and type 2 diabetes. Here, we show that the secondary structure of the peptide uperin 3.5 directs the kinetics and mechanism of amyloid fibrillar aggregation. Uperin 3.5 variants were investigated using thioflavin T fluorescence assays, circular dichroism spectroscopy, and structure prediction methods. Our results suggest that those peptide variants with a strong propensity to form an α-helical secondary structure under physiological conditions are more likely to aggregate into amyloid fibrils than peptides in an unstructured or “random coil” conformation. This conclusion is in good agreement with the hypothesis that an α-helical transition state is required for peptide aggregation into amyloid fibrils. Specifically, uperin 3.5 variants in which charged amino acids were replaced by alanine were richer in α-helical content, leading to enhanced aggregation compared to that of wild type uperin 3.5. However, the addition of 2,2,2-trifluoroethanol as a major co-solute or membrane-mimicking phospholipid environments locked uperin 3.5 to the α-helical conformation preventing amyloid aggregation. Strategies for stabilizing peptides into their α-helical conformation could provide therapeutic approaches for overcoming peptide aggregation-related diseases. The impact of the physiological environment on peptide secondary structure could explain aggregation processes in a cellular environment.
dc.description.sponsorshipThis work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Project 189853844, SFB-TRR 102, B1). T.J. thanks the FriedrichEbert-Stiftung for a Ph.D. fellowship and the Australian Government, Department of Education and Training, and Scope Global for the support through a 2018 Endeavour Research Fellowship. J.A.C.’s work was supported by a grant (1068087) from the National Health and Medical Research Council of Australia. Y.H. acknowledges the support by the Australian Research Council (DE170100058).
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherAmerican Chemical Society
dc.rights© 2019 American Chemical Society
dc.sourceBiochemistry
dc.titleThe Kinetics of Amyloid Fibrillar Aggregation of Uperin 3.5 Is Directed by the Peptide's Secondary Structure
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume58
dc.date.issued2019
local.identifier.absfor030400 - MEDICINAL AND BIOMOLECULAR CHEMISTRY
local.identifier.ariespublicationu6048437xPUB787
local.publisher.urlhttps://pubs.acs.org/
local.type.statusPublished Version
local.contributor.affiliationJohn, Torsten, Monash University
local.contributor.affiliationDealey, Tiara J A, Monash University
local.contributor.affiliationGray, Nicholas P., Monash University
local.contributor.affiliationPatil, Nitin A, University of Melbourne
local.contributor.affiliationHossain, Mohammed A., The University of Melbourne
local.contributor.affiliationAbel, Bernd, Leibniz Institute of Surface Engineering
local.contributor.affiliationCarver, John, College of Science, ANU
local.contributor.affiliationHong, Yuning, La Trobe University
local.contributor.affiliationMartin, Lisandra, Monash University
local.description.embargo2037-12-31
dc.relationhttp://purl.org/au-research/grants/nhmrc/1068087
dc.relationhttp://purl.org/au-research/grants/arc/DE170100058
local.bibliographicCitation.startpage3656
local.bibliographicCitation.lastpage3668
local.identifier.doi10.1021/acs.biochem.9b00536
dc.date.updated2019-11-25T08:05:21Z
local.identifier.scopusID2-s2.0-85071728566
CollectionsANU Research Publications

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