Role of Zinc in Human Islet Amyloid Polypeptide Aggregation

作者：Jeffrey Brender, Kevin Hartman, Ravi Prakash Reddy Nanga, Nataliya Popovych, Roberto de la Salud Bea, Subramanian Vivekanandan, E. Neil G. Marsh, Ayyalusamy Ramamoorthy · 发表于：Journal of the American Chemical Society · 年份：2010 · DOI：10.1021/ja1007867 · 被引用次数：243 · 研究领域：Alzheimer's disease research and treatments、Drug Transport and Resistance Mechanisms、Trace Elements in Health

Human Islet Amyloid Polypeptide (hIAPP) is a highly amyloidogenic protein found in islet cells of patients with type II diabetes. Because hIAPP is highly toxic to beta-cells under certain conditions, it has been proposed that hIAPP is linked to the loss of beta-cells and insulin secretion in type II diabetics. One of the interesting questions surrounding this peptide is how the toxic and aggregation prone hIAPP peptide can be maintained in a safe state at the high concentrations that are found in the secretory granule where it is stored. We show here zinc, which is found at millimolar concentrations in the secretory granule, significantly inhibits hIAPP amyloid fibrillogenesis at concentrations similar to those found in the extracellular environment. Zinc has a dual effect on hIAPP fibrillogenesis: it increases the lag-time for fiber formation and decreases the rate of addition of hIAPP to existing fibers at lower concentrations, while having the opposite effect at higher concentrations. Experiments at an acidic pH which partially neutralizes the change in charge upon zinc binding show inhibition is largely due to an electrostatic effect at His18. High-resolution structures of hIAPP determined from NMR experiments confirm zinc binding to His18 and indicate zinc induces localized disruption of the secondary structure of IAPP in the vicinity of His18 of a putative helical intermediate of IAPP. The inhibition of the formation of aggregated and toxic forms of hIAPP by zinc provid...