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. 2015 Feb 4:5:8240.
doi: 10.1038/srep08240.

Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration

Affiliations

Inhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration

Praveen Nedumpully-Govindan et al. Sci Rep. .

Abstract

While islet amyloid polypeptide (IAPP) aggregation is associated with β-cell death in type-II diabetes (T2D), environmental elements of β-cell granules - e.g. high concentrations of insulin and Zn(2+) - inhibit IAPP aggregation in healthy individuals. The inhibition by insulin is experimentally known, but the role of Zn(2+) is controversial as both correlations and anti-correlations at the population level are observed between T2D risk and the activity of a β-cell specific zinc ion transporter, ZnT8. Since Zn(2+) concentration determines insulin oligomer equilibrium, we computationally investigated interactions of IAPP with different insulin oligomers and compared with IAPP homodimer formation. We found that IAPP binding with insulin oligomers competes with the formation of both higher-molecular-weight insulin oligomers and IAPP homodimers. Therefore, zinc deficiency due to loss-of-function ZnT8 mutations shifts insulin oligomer equilibrium toward zinc-free monomers and dimers, which bind IAPP monomers more efficiently compared to zinc-bound hexamers. The hetero-molecular complex formation prevents IAPP from self-association and subsequent aggregation, reducing T2D risk.

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Figures

Figure 1
Figure 1. hIAPP and rIAPP monomer structures.
(A) The specific heat, Cv, plots for hIAPP and rIAPP monomers. The hIAPP monomer lacks any peak in the Cv plot while the rIAPP monomer has a well-defined melting temperature. Representative snapshots of hIAPP (B) and rIAPP (C) conformations are taken from DMD simulations at T = 0.55 kcal/(mol·KB). Compared to hIAPP, rIAPP has an ordered 3D folded structure. Six residues different between hIAPP and rIAPP are highlighted in stick representation.
Figure 2
Figure 2. hIAPP homodimer formation.
(A) The specific heat plot of hIAPP dimer has a peak, which is different from its monomer. (B) Inter-molecular contact frequencies of hIAPP residues when they form dimers at T = 0.6 kcal/(mol·KB). Many of the frequent contacts are along the diagonal, indicating a favorable parallel association of two monomers. (C) A typical dimer structure corresponding to the centroid of one of the largest clusters shows a parallel association of helices formed by N-terminal residues. Residues 22–29 in orange, which are amyloidogenic, form a β-sheet in the dimer. The hotspot residues making frequent contacts are highlighted in stick representation.
Figure 3
Figure 3. hIAPP–insulin dimerization.
(A) The specific heat plot for insulin–hIAPP complex has two peaks corresponding to insulin–hIAPP unbinding and insulin melting. (B) The inter-molecular contact frequencies between insulin and hIAPP residues at T = 0.6 kcal/(mol·KB). Insulin A-chain (21 residues) and B-chain (30 residues), separated by a dotted orange line, are numbered sequentially. (C) A typical structure of the hIAPP-insulin complex is derived from DMD simulations. The amyloidogenic residues of hIAPP (residues 22–29) are shown in orange. The residues of insulin important for binding hIAPP are highlighted in stick representation. (D) The residues of an insulin monomer are colored according to hIAPP binding frequencies in the structure of an insulin hexamer. The view with 180° rotation is also presented. The residues with strong hIAPP-binding are located at the insulin monomer–monomer interface.
Figure 4
Figure 4. Insulin dimer–hIAPP contact.
(A) The inter-molecular contact frequency map between insulin dimer (averaged over two monomers) and hIAPP. (B) The residues of an insulin dimer are colored according to the hIAPP-binding frequency in the 3D structure of the insulin hexamer. For each residue in A-chain (C) and B-chain (D), the average number of contacts with hIAPP is obtained from DMD simulations.
Figure 5
Figure 5. The relationship between hIAPP aggregation pathway and insulin oligomer equilibrium.
hIAPPs (in yellow) form dimers first, and finally β-strand rich aggregates. Insulins (in gray) are at oligomer equilibrium between monomer, dimer and hexamer. Two zinc ions are required for the coordination of three dimers to form the hexamer, and thus the concentration of zinc ion governs the insulin oligomer equilibrium. Our DMD simulations suggest that hIAPP monomer preferentially binds to insulin monomer and dimer. Binding of hIAPP monomers by insulin monomers and dimers competes with hIAPP homodimer formation. With loss-of-function mutations in ZnT8, the deficiency of zinc ions shift the insulin oligomer equilibrium toward monomers and dimers, which sequester hIAPP monomers and inhibit hIAPP self-association and aggregation.

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