title: The redox environment triggers conformational changes and aggregation of hIAPP in Type II Diabetes.
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 β-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 α-helical structure which is lacking in the reduced state of hIAPP. In healthy cells, this residual structure prevents the conversion into amyloidogenic aggregates.
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.|Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM), Germany.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Rodriguez Camargo
authors.affiliation: Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, Brno 62500, Czech Republic.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tripsianes
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
authors.forename: Katalin
authors.initials: K
authors.lastname: Buday
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg 85764, Germany.
authors.forename: Andras
authors.initials: A
authors.lastname: Franko
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.|Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM), Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Göbl
authors.affiliation: Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM), Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hartlmüller
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.|Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM), Germany.
authors.forename: Riddhiman
authors.initials: R
authors.lastname: Sarkar
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mettenleiter
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schulz
authors.affiliation: Max-Delbrück-Center Berlin (MDC), Robert-Rössle-Str. 10, Berlin 13125, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Böddrich
authors.affiliation: Synaptic Systems GmbH, Rudolf-Wissell-Straße 28, Göttingen, 37079, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Erck
authors.affiliation: Synaptic Systems GmbH, Rudolf-Wissell-Straße 28, Göttingen, 37079, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Martens
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
authors.forename: Axel Karl
authors.initials: AK
authors.lastname: Walch
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.|Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM), Germany.|Institute of Molecular Biology &Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Madl
authors.affiliation: Max-Delbrück-Center Berlin (MDC), Robert-Rössle-Str. 10, Berlin 13125, Germany.
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.|German Center for Diabetes Research (DZD e.V.), Neuherberg 85764, Germany.|Technische Universität München, Center of Life and Food Sciences Weihenstephan, Freising 85354, Germany.
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg 85764, Germany.|Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM), Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Reif
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D066263:Protein Aggregation, Pathological; D011487:Protein Conformation
chemical_list: D058228:Islet Amyloid Polypeptide