Zn(II) ions co-secreted with insulin suppress inherent amyloidogenic properties of monomeric insulin.
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 Zn(2)Insulin(6) hexamer, which assures osmotic stability of vesicles and prevents fibrillation of the peptide. However, after release from the pancreatic beta-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 fibrillation of monomeric insulin is unknown, however, it might prevent insulin fibrillation. We showed that Zn(II) inhibits fibrillation of monomeric insulin at physiological pH values by forming a soluble Zn(II)-insulin complex. The inhibitory effect of Zn(II) ions is very strong at pH 7.3 (IC(50)=3.5 microM), whereas at pH 5.5 it progressively weakens, pointing towards participation of the histidine residue(s) in complex formation. The results obtained indicate that Zn(II) ions might suppress fibrillation of insulin at its release sites and in circulation. It is hypothesized that misfolded oligomeric intermediates occurring in the insulin fibrillation pathway, especially in zinc-deficient conditions, might induce autoantibodies against insulin, which leads to beta-cell damage and autoimmune Type 1 diabetes.
Noormägi
Andra
A
Department of Gene Technology, Tallinn University of Technology, Estonia.
Gavrilova
Julia
J
Smirnova
Julia
J
Tõugu
Vello
V
Palumaa
Peep
P
D000465:Algorithms; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism; D007477:Ions; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D021241:Spectrometry, Mass, Electrospray Ionization; D013696:Temperature; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
D000682:Amyloid; D007328:Insulin; D007477:Ions; D009942:Organometallic Compounds; D015032:Zinc