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The role of copper(ii) in the aggregation of human amylin

Sinopoli, Alessandro; Magrì, Antonio; Milardi, Danilo; Pappalardo, Matteo; Pucci, Pietro; Flagiello, Angela; Titman, Jeremy J.; Nicoletti, Vincenzo G.; Caruso, Giuseppe; Pappalardo, Giuseppe; Grasso, Giuseppe

Authors

Alessandro Sinopoli

Antonio Magrì

Danilo Milardi

Matteo Pappalardo

Pietro Pucci

Angela Flagiello

Jeremy J. Titman

Vincenzo G. Nicoletti

Giuseppe Caruso

Giuseppe Pappalardo

Giuseppe Grasso



Abstract

Amylin is the 37-residue peptide hormone produced by the islet β-cells in the pancreas and the formation of amylin aggregates is strongly associated with β-cells degeneration in type 2 diabetes, as demonstrated by more than 95% of patients exhibiting amylin amyloid upon autopsy. It is widely recognized that metal ions such as copper(II) have been implicated in the aggregation process of amyloidogenic peptides such as Aβ and α-synuclein and there is evidence that also amylin self-assembly is largely affected by copper(II). For this reason, in this work, the role of copper(II) in the aggregation of amylin has been investigated by several different experimental approaches. Mass spectrometric investigations show that copper(II) induces significant changes in the amylin structure which decrease the protein fibrillogenesis as observed by ThT measurements. Accordingly, solid-state NMR experiments together with computational analysis carried out on a model amylin fragment confirmed the non fibrillogenic nature of the copper(II) induced aggregated structure. Finally, the presence of copper(II) is also shown to have a major influence on amylin proneness to be degraded by proteases and cytotoxicity studies on different cell cultures are reported.

Journal Article Type Article
Publication Date Oct 1, 2014
Journal Metallomics
Print ISSN 1756-5901
Electronic ISSN 1756-591X
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 6
Issue 10
Pages 1841-1852
APA6 Citation Sinopoli, A., Magrì, A., Milardi, D., Pappalardo, M., Pucci, P., Flagiello, A., …Grasso, G. (2014). The role of copper(ii) in the aggregation of human amylin. Metallomics, 6(10), 1841-1852. https://doi.org/10.1039/c4mt00130c
DOI https://doi.org/10.1039/c4mt00130c
Publisher URL http://pubs.rsc.org/en/content/articlelanding/2014/mt/c4mt00130c#!divAbstract
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information : This document is CrossCheck deposited; : Supplementary Information; : The Royal Society of Chemistry has an exclusive publication licence for this journal; OPEN ACCESS: The accepted version of this article will be made freely available after a 12 month embargo period; : Received 6 May 2014; Accepted 24 July 2014; Accepted Manuscript published 24 July 2014; Advance Article published 1 August 2014; Version of Record published 1 October 2014

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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