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Impaired Processing of Human Pro-Islet Amyloid Polypeptide Is Not a Causative Factor for Fibril Formation or Membrane Damage in Vitro

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    Impaired Processing of Human Pro-Islet Amyloid Polypeptide Is Not a Causative Factor for Fibril Formation or Membrane Damage in Vitro
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    ‡ Department of Chemical Biology and Organic Chemistry, Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
    § Department of Metabolic and Endocrine Diseases, Division of Biomedical Genetics, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands
    ∥ Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands
    ⊥ Department of Molecular Cell Biology, Electron Microscopy Utrecht, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
    *To whom correspondence should be addressed: Department of Chemical Biology and Organic Chemistry, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands. Telephone: +31 30 2533345. Fax: +31 30 2533969. E-mail: [email protected]
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    Biochemistry

    Cite this: Biochemistry 2009, 48, 46, 10918–10925
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    https://doi.org/10.1021/bi901076d
    Published October 9, 2009
    Copyright © 2009 American Chemical Society
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    Abstract

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    Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils in pancreatic islets of patients with type 2 diabetes mellitus (DM2). hIAPP is synthesized by islet β-cells initially as a preprohormone, processing of which occurs in several steps. It has been suggested that in DM2 this processing is defective and that aggregation of the processing intermediates prohIAPP and prohIAPP1−48 may represent the initial step in formation of islet amyloid. Here we investigate this possibility by analyzing the aggregation, the structure, and the membrane interaction of mature hIAPP and its precursors, prohIAPP and prohIAPP1−48, in vitro. Our data reveal that both precursors form amyloid fibrils in solution but not in the presence of membranes. This inhibition is in contrast to the catalyzing effect of membranes on fibril formation of mature hIAPP. Importantly, in the presence of membranes, both precursors are able to inhibit fibrillogenesis of mature hIAPP. These differences in behavior between mature hIAPP and its precursors are most likely related to differences in their mode of membrane insertion. Both precursors insert efficiently and adopt an α-helical structure even with a high lipid/peptide ratio, while mature hIAPP rapidly adopts a β-sheet conformation. Furthermore, while mature hIAPP affects the barrier properties of lipid vesicles, neither of the precursors is able to induce membrane leakage. Our study suggests that the hIAPP precursors prohIAPP and prohIAPP1−48 do not serve as amyloid initiators but rather prevent aggregation and membrane damage of mature hIAPP in early stages of its biosynthesis and intracellular transport.

    Copyright © 2009 American Chemical Society

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    This article is cited by 20 publications.

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    16. Ping Cao, Andisheh Abedini, Daniel P Raleigh. Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology. Current Opinion in Structural Biology 2013, 23 (1) , 82-89. https://doi.org/10.1016/j.sbi.2012.11.003
    17. Safia Costes, Ralf Langen, Tatyana Gurlo, Aleksey V. Matveyenko, Peter C. Butler. β-Cell Failure in Type 2 Diabetes: A Case of Asking Too Much of Too Few?. Diabetes 2013, 62 (2) , 327-335. https://doi.org/10.2337/db12-1326
    18. Shanghao Li, Miodrag Micic, Jhony Orbulescu, Jeffrey D. Whyte, Roger M. Leblanc. Human islet amyloid polypeptide at the air–aqueous interface: a Langmuir monolayer approach. Journal of The Royal Society Interface 2012, 9 (76) , 3118-3128. https://doi.org/10.1098/rsif.2012.0368
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    20. Per Westermark, Arne Andersson, Gunilla T. Westermark. Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus. Physiological Reviews 2011, 91 (3) , 795-826. https://doi.org/10.1152/physrev.00042.2009
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    Biochemistry

    Cite this: Biochemistry 2009, 48, 46, 10918–10925
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi901076d
    Published October 9, 2009
    Copyright © 2009 American Chemical Society
    Request reuse permissions

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