Zn(II) ions co-secreted with insulin suppress inherent amyloidogenic properties of monomeric insulin
Résumé
Insulin, a 51-residue peptide hormone is an intrinsically amyloidogenic peptide, forming amyloid fibrils in vitro. In the secretory granules insulin is densely packed together with Zn(II) into crystals of Zn2Insulin6 hexamer, which assures osmotic stability of vesicles and prevents fibrillization of the peptide. However, after release from the pancreatic β-cells insulin dissociates into active monomers, which tend to fibrillize not only at acidic but also at physiological pH values. The effect of co-secreted Zn(II) ions on the fibrillization of monomeric insulin is unknown, however, it might prevent insulin fibrillization. We showed that Zn(II) inhibits fibrillization of monomeric insulin at physiological pH values by forming a soluble Zn(II)Insulin complex. Inhibitory effect of Zn(II) ions is very strong at pH 7.3 (IC50=3.5 μM), whereas at pH 5.5 it progressively weakens, pointing towards participation of the His residue(s) in complex formation. Obtained results indicate that Zn(II) ions might suppress fibrillization of insulin at its release sites and in circulation. It is hypothesized that misfolded oligomeric intermediates occurring in insulin fibrillization pathway, especially in zinc-deficient conditions, might induce autoantibodies against insulin, which leads to β-cell damage and autoimmune type I diabetes.
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