Promotion or Inhibition of Islet Amyloid Polypeptide Aggregation by Zinc Coordination Depends on Its Relative Concentration

Abstract

Zinc is reported to play a complex role in islet amyloid polypeptide (IAPP) aggregation, which is associated with β-cell death in type II diabetes (T2D). Depending on their relative concentrations in vitro, zinc could either promote or inhibit IAPP aggregation. Interestingly, genomewide association studies suggested both positive and negative correlations between T2D risks and activities of a β-cell-specific zinc transporter upon mutations, which determines zinc concentration in vivo. To decipher the effect of zinc coordination on IAPP aggregation, we performed atomistic discrete molecular dynamics simulations to systemically study aggregation propensities of zinc-coordinated IAPP oligomers with different molecular weights (MWs), whose populations are determined by zinc concentration. We find that at low zinc:IAPP stoichiometry, zinc coordination promotes aggregation by forming high-MW oligomers. The aggregation is inhibited when the stoichiometry increases and zinc binds individual peptides. Our computationally derived predictions are validated by the complementary thioflavin-T fluorescence assay measuring the dependence of IAPP aggregation on a wide range of zinc concentrations. Our combined computational and experimental study offers detailed mechanistic insight into the complex role of zinc on IAPP aggregation and T2D development.

Zinc-coordination and C-peptide complexation: a potential mechanism for the endogenous inhibition of IAPP aggregation

“…Here, the observed concentration-dependence for zinc on IAPP aggregation is consistent with our previous studies. 16 The experimentally observed 2.7:1 ratio with maximum aggregation inhibition is close to the predicted 2:1 molecular ratio between IAPP and C-peptide in the aggregation-incompetent heterotrimer (Figs. 1, 2).…”

“…Electrostatic repulsion between protonated histidine18 (His18) was found responsible for inhibiting IAPP aggregation at low pH. 14,16 Previous studies by our group and others 17–19 offered molecular insights to the binding of insulin with IAPP for understanding the inhibition mechanism. The inhibition of IAPP aggregation by insulin has also been found to suppress the aggregation-induced membrane disruption.…”

“…23–25 Discrete molecular dynamics (DMD) simulations of zinc-coordinated IAPP oligomers with different molecular weights (MWs) 16 revealed that high MW IAPP oligomers (enriched at low zinc/IAPP stoichiometry) could form inter-peptide hydrogen bonds and enhance the formation of β-rich aggregates, but electrostatic repulsions between zinc-bound IAPP monomers (enriched at high zinc/IAPP stoichiometry) reduced IAPP self-association and aggregation as in the case of protonated His18 at low pH. 14 While DMD simulations offered an explanation for the concentration-dependent effect of zinc on IAPP aggregation as observed experimentally, 16,22–26 these results also suggest that zinc binding alone is insufficient for the endogenous inhibition of IAPP aggregation. C-peptide, on the other hand, was found to promote IAPP aggregation in vitro .…”

Implications of peptide assemblies in amyloid diseases

“…186 ). Combining DMD simulations with experimental characterizations 179 , Govindan et al developed an alternative model that was consistent with the experimentally-observed concentration-dependent effect of zinc on IAPP aggregation. At low zinc/IAPP stoichiometry, the IAPP oligomers cross-linked by zinc were aggregation-prone due to high local peptide concentrations (Fig.…”

“…(c) A representative IAPP tetramer with His18 (highlighted as sticks in pink) coordinated by a Zn 2+ (blue sphere) from DMD simulations. 179 The amyloidogenic sequences from each IAPP monomer are highlighted in rainbow colors. (d) A mechanistic scheme demonstrating the dependence of IAPP aggregation on relative zinc concentration.…”