Role of Zinc in Human Islet Amyloid Polypeptide Aggregation

Abstract

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. Highresolution 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 provides a possible mechanism between the recent discovery of linkage between deleterious mutations in the SLC30A8 zinc transporter, which transports zinc into the secretory granule, and type II diabetes.

The β-cell assassin: IAPP cytotoxicity

“…However, under normal conditions it is likely that the granule peptides also have influences on each other. Interaction in vitro of insulin, c-peptide, proinsulin and zinc with hIAPP have been investigated and shown to have variable effects on IAPP fibrillogenesis; high concentrations of zinc accelerate, but lower concentrations reduce fibril formation (Westermark et al 1996, Brender et al 2010. Human proinsulin and insulin formed heteromolecular complexes with hIAPP and prevented fibrillogenesis (Jaikaran et al 2004, Larson & Miranker 2004, Knight et al 2008, Wiltzius et al 2009).…”

Human islet amyloid polypeptide at the air–aqueous interface: a Langmuir monolayer approach

“…One possible reason for this observation could be that it might take a longer time for the hIAPP molecules to form aggregates than the time needed for the Langmuir monolayer experiment. It typically took a few hours to detect fibril formation by thioflavin T fluorescence in solution [27,32,34], but one set of Langmuir monolayer experiments needed only 30-40 min. Another possibility could be that some aggregation did form, but the surface pressure-area isotherm could not detect it.…”

Role of heavy metals in human health and particularly in respect to diabetic patients

“…Zn plays a key role in the storage and secretion of insulin, which then increases the uptake of glucose (Kazi et al, 2008;Rungby, 2010). The decreased plasma level of Zn adversely affects the ability of islet cells to produce and secrete insulin (Brender et al, 2010;Rungby, 2010). The Zn transporter (ZnT8) is a key protein for the regulation of insulin secretion from the pancreatic β-cells.…”