The redox environment triggers conformational changes and aggregation of hIAPP in Type II Diabetes

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.

• Publication year

  2017

• Venue

  Scientific Reports

• Publication date

  2017-03-13

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/srep44041PMID 28287098PMCID 5347123
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Author contributions

  2019cited by this paper
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• Structural Characterization of Fibrils from Recombinant Human Islet Amyloid Polypeptide by Solid-State NMR: The Central FGAILS Segment Is Part of the β-Sheet Core

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• The chaperone αB-crystallin uses different interfaces to capture an amorphous and an amyloid client

  2015cited by this paper
• Cloning, expression and purification of the human Islet Amyloid Polypeptide (hIAPP) from Escherichia coli.

  2015influential reference
• Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetes-associated specific antibodies

  2014influential reference
• Role of islet β cell autophagy in the pathogenesis of diabetes.

  2014cited by this paper
• pH dependence of amylin fibrillization.

  2014influential reference
• Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity.

  2014cited by this paper
• Endoplasmic reticulum: reduced and oxidized glutathione revisited

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  2013cited by this paper
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  2011influential reference
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  2011influential reference
• The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation

  2011cited by this paper
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  2011cited by this paper
• Islet amyloid polypeptide, islet amyloid, and diabetes mellitus.

  2011influential reference
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  2010cited by this paper
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  2009cited by this paper
• Atomic structures of IAPP (amylin) fusions suggest a mechanism for fibrillation and the role of insulin in the process

  2009influential reference
• Helix stabilization precedes aqueous and bilayer-catalyzed fiber formation in islet amyloid polypeptide.

  2009influential reference
• Amyloid formation by globular proteins under native conditions.

  2009influential reference
• Dynamic α-Helix Structure of Micelle-bound Human Amylin*

  2009influential reference
• Peptide conformation and supramolecular organization in amylin fibrils: constraints from solid-state NMR.

  2007cited by this paper
• Pancreatic Islet Amyloid and Diabetes

  2007cited by this paper
• Direct detection of transient alpha-helical states in islet amyloid polypeptide.

  2007cited by this paper
• Direct detection of transient α‐helical states in islet amyloid polypeptide

  2007influential reference
• Redox-regulated conformational changes in an SH3 domain.

  2007influential reference
• Induction of endoplasmic reticulum stress-induced beta-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide.

  2007cited by this paper
• Intracellular amyloid-like deposits contain unprocessed pro-islet amyloid polypeptide (proIAPP) in beta cells of transgenic mice overexpressing the gene for human IAPP and transplanted human islets

  2006influential reference
• Diabetic changes in the redox status of the microsomal protein folding machinery.

  2005cited by this paper
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  2005influential reference
• Secretory granules

  2005influential reference
• The CCPN data model for NMR spectroscopy: Development of a software pipeline

  2005cited by this paper
• Contribution of the intrinsic disulfide to the assembly mechanism of islet amyloid

  2005influential reference
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  2005influential reference
• Endoplasmic reticulum stress: cell life and death decisions.

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  2004cited by this paper
• Automated NMR structure calculation with CYANA.

  2004influential reference
• Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

  2004influential reference
• RelA life and death decisions.

  2004influential reference
• Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes.

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• β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes

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  2003influential reference
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  2002cited by this paper
• Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.

  2001influential reference
• Competition between glutathione and protein thiols for disulphide-bond formation

  1999influential reference
• Heteronuclear multidimensional NMR experiments for the structure determination of proteins in solution employing pulsed field gradients

  1999cited by this paper
• Protein backbone angle restraints from searching a database for chemical shift and sequence homology

  1999cited by this paper
• Conformational transitions of islet amyloid polypeptide (IAPP) in amyloid formation in vitro.

  1999influential reference
• The Rising Global Burden of Diabetes and its Complications: Estimates and Projections to the Year 2010

  1997cited by this paper
• Effects of beta cell granule components on human islet amyloid polypeptide fibril formation

  1996influential reference
• NMRPipe: A multidimensional spectral processing system based on UNIX pipes

  1995cited by this paper
• An efficient experiment for sequential backbone assignment of medium-sized isotopically enriched proteins

  1992influential reference
• Manipulating disulfide bond formation and protein folding in the endoplasmic reticulum.

  1992influential reference
• Islet Amyloid Polypeptide and Insulin Secretion From Isolated Perfused Pancreas of Fed, Fasted, Glucose-Treated, and Dexamethasone-Treated Rats

  1991influential reference
• The insulin secretory granule

  1989influential reference
• Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients.

  1987influential reference

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