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dc.contributor.authorRodriguez Camargo, Diana C
dc.contributor.authorChia, Sean
dc.contributor.authorMenzies, Joseph
dc.contributor.authorMannini, Benedetta
dc.contributor.authorMeisl, Georg
dc.contributor.authorLundqvist, Martin
dc.contributor.authorPohl, Christin
dc.contributor.authorBernfur, Katja
dc.contributor.authorLattanzi, Veronica
dc.contributor.authorHabchi, Johnny
dc.contributor.authorCohen, Samuel Ia
dc.contributor.authorKnowles, Tuomas
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorLinse, Sara
dc.date.accessioned2021-11-22T14:38:10Z
dc.date.available2021-11-22T14:38:10Z
dc.date.issued2021
dc.date.submitted2021-08-12
dc.identifier.issn2296-889X
dc.identifier.other757425
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330819
dc.description.abstractThe aggregation of the human islet amyloid polypeptide (IAPP) is associated with diabetes type II. A quantitative understanding of this connection at the molecular level requires that the aggregation mechanism of IAPP is resolved in terms of the underlying microscopic steps. Here we have systematically studied recombinant IAPP, with amidated C-terminus in oxidised form with a disulphide bond between residues 3 and 7, using thioflavin T fluorescence to monitor the formation of amyloid fibrils as a function of time and IAPP concentration. We used global kinetic analyses to connect the macroscopic measurements of aggregation to the microscopic mechanisms, and show that the generation of new aggregates is dominated by the secondary nucleation of monomers on the fibril surface. We then exposed insulinoma cells to aliquots extracted from different time points of the aggregation process, finding the highest toxicity at the midpoint of the reaction, when the secondary nucleation rate reaches its maximum. These results identify IAPP oligomers as the most cytotoxic species generated during IAPP aggregation, and suggest that compounds that target secondary nucleation of IAPP could be most effective as therapeutic candidates for diabetes type II.
dc.languageen
dc.publisherFrontiers Media SA
dc.subjectMolecular Biosciences
dc.subjectself-assembly
dc.subjectamyloid formation
dc.subjectreaction mechanism
dc.subjectoptical spectroscopy
dc.subjectpeptide purification
dc.titleSurface-Catalyzed Secondary Nucleation Dominates the Generation of Toxic IAPP Aggregates.
dc.typeArticle
dc.date.updated2021-11-22T14:38:09Z
prism.publicationNameFront Mol Biosci
prism.volume8
dc.identifier.doi10.17863/CAM.78262
dcterms.dateAccepted2021-10-12
rioxxterms.versionofrecord10.3389/fmolb.2021.757425
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidMeisl, Georg [0000-0002-6562-7715]
dc.contributor.orcidKnowles, Tuomas [0000-0002-7879-0140]
dc.contributor.orcidVendruscolo, Michele [0000-0002-3616-1610]
dc.identifier.eissn2296-889X
cam.issuedOnline2021-11-01


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