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The redox environment triggers conformational changes and aggregation of hIAPP in type II diabetes

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Item Type:Article
Title:The redox environment triggers conformational changes and aggregation of hIAPP in type II diabetes
Creators Name:Rodriguez Camargo, D.C. and Tripsianes, K. and Buday, K. and Franko, A. and Göbl, C. and Hartlmüller, C. and Sarkar, R. and Aichler, M. and Mettenleiter, G. and Schulz, M. and Böddrich, A. and Erck, C. and Martens, H. and Walch, A.K. and Madl, T. and Wanker, E.E. and Conrad, M. and de Angelis, M.H. and Reif, B.
Abstract:Type II diabetes (T2D) is characterized by diminished insulin production and resistance of cells to insulin. Among others, endoplasmic reticulum (ER) stress is a principal factor contributing to T2D and induces a shift towards a more reducing cellular environment. At the same time, peripheral insulin resistance triggers the over-production of regulatory hormones such as insulin and human islet amyloid polypeptide (hIAPP). We show that the differential aggregation of reduced and oxidized hIAPP assists to maintain the redox equilibrium by restoring redox equivalents. Aggregation thus induces redox balancing which can assist initially to counteract ER stress. Failure of the protein degradation machinery might finally result in {beta}-cell disruption and cell death. We further present a structural characterization of hIAPP in solution, demonstrating that the N-terminus of the oxidized peptide has a high propensity to form an {alpha}-helical structure which is lacking in the reduced state of hIAPP. In healthy cells, this residual structure prevents the conversion into amyloidogenic aggregates.
Keywords:Type 2, Diabetes Mellitus, Endoplasmic Reticulum Stress, Islet Amyloid Polypeptide, Inbred BALB C, Mice, Transgenic, Mice, Oxidation-Reduction, Pathological, Protein Aggregation, Protein Conformation, Animals, Mice
Source:Scientific Reports
Publisher:Nature Publishing Group
Page Range:44041
Date:13 March 2017
Official Publication:https://doi.org/10.1038/srep44041
PubMed:View item in PubMed

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