Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep44041
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Funding
- Deutsche Forschungsgemeinschaft, DFG [SFB-1035]
- Helmholtz-Gemeinschaft
- DFG [Re1435]
- Center for Integrated Protein Science Munich (CIPS-M)
- Ministry of Education, Youth and Sports of the Czech Republic [LQ1601]
- Bavarian Ministry of Sciences, Research and the Arts (Bavarian Molecular Biosystems Research Network)
- DFG (Emmy Noether program) [MA 5703/1-1, CO 291/5-1]
- Austrian Science Fund [FWF: P28854]
- postdoctoral fellowship program (PFP) of the Helmholtz-Zentrum-Munchen
- HELENA graduate school
- TUM graduate school
- Austrian Science Fund (FWF) [P28854] Funding Source: Austrian Science Fund (FWF)
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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.
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