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Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly
Human islet amyloid polypeptide (hIAPP) self-assembles into amyloid fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism of amyloid assembly of wild-type hIAPP and its more amyloidogenic natural variant S20G. We show...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8873464/ https://www.ncbi.nlm.nih.gov/pubmed/35210421 http://dx.doi.org/10.1038/s41467-022-28660-7 |
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author | Xu, Yong Maya-Martinez, Roberto Guthertz, Nicolas Heath, George R. Manfield, Iain W. Breeze, Alexander L. Sobott, Frank Foster, Richard Radford, Sheena E. |
author_facet | Xu, Yong Maya-Martinez, Roberto Guthertz, Nicolas Heath, George R. Manfield, Iain W. Breeze, Alexander L. Sobott, Frank Foster, Richard Radford, Sheena E. |
author_sort | Xu, Yong |
collection | PubMed |
description | Human islet amyloid polypeptide (hIAPP) self-assembles into amyloid fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism of amyloid assembly of wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that the aggregation of both peptides involves primary nucleation, secondary nucleation and elongation. We also report the discovery of two structurally distinct small-molecule modulators of hIAPP assembly, one delaying the aggregation of wt hIAPP, but not S20G; while the other enhances the rate of aggregation of both variants at substoichiometric concentrations. Investigation into the inhibition mechanism(s) using chemical kinetics, native mass spectrometry, fluorescence titration, SPR and NMR revealed that the inhibitor retards primary nucleation, secondary nucleation and elongation, by binding peptide monomers. By contrast, the accelerator predominantly interacts with species formed in the lag phase. These compounds represent useful chemical tools to study hIAPP aggregation and may serve as promising starting-points for the development of therapeutics for T2D. |
format | Online Article Text |
id | pubmed-8873464 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-88734642022-03-17 Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly Xu, Yong Maya-Martinez, Roberto Guthertz, Nicolas Heath, George R. Manfield, Iain W. Breeze, Alexander L. Sobott, Frank Foster, Richard Radford, Sheena E. Nat Commun Article Human islet amyloid polypeptide (hIAPP) self-assembles into amyloid fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism of amyloid assembly of wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that the aggregation of both peptides involves primary nucleation, secondary nucleation and elongation. We also report the discovery of two structurally distinct small-molecule modulators of hIAPP assembly, one delaying the aggregation of wt hIAPP, but not S20G; while the other enhances the rate of aggregation of both variants at substoichiometric concentrations. Investigation into the inhibition mechanism(s) using chemical kinetics, native mass spectrometry, fluorescence titration, SPR and NMR revealed that the inhibitor retards primary nucleation, secondary nucleation and elongation, by binding peptide monomers. By contrast, the accelerator predominantly interacts with species formed in the lag phase. These compounds represent useful chemical tools to study hIAPP aggregation and may serve as promising starting-points for the development of therapeutics for T2D. Nature Publishing Group UK 2022-02-24 /pmc/articles/PMC8873464/ /pubmed/35210421 http://dx.doi.org/10.1038/s41467-022-28660-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Xu, Yong Maya-Martinez, Roberto Guthertz, Nicolas Heath, George R. Manfield, Iain W. Breeze, Alexander L. Sobott, Frank Foster, Richard Radford, Sheena E. Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly |
title | Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly |
title_full | Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly |
title_fullStr | Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly |
title_full_unstemmed | Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly |
title_short | Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly |
title_sort | tuning the rate of aggregation of hiapp into amyloid using small-molecule modulators of assembly |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8873464/ https://www.ncbi.nlm.nih.gov/pubmed/35210421 http://dx.doi.org/10.1038/s41467-022-28660-7 |
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