Understanding the Endogenous Inhibition of IAPP Aggregation

Abstract

Amyloid aggregation of islet amyloid polypeptide (IAPP) is associated with β-cell death in type-2 diabetes (T2D)[1]. IAPP readily forms amyloid fibrils in vitro at μM concentrations. However, no apparent IAPP aggregates are observed in healthy individuals where IAPP is stored in β-cell granules at mM concentrations. Therefore, physiological conditions of β-cell granules endogenously inhibit the amyloid aggregation of IAPP. Disruption of the inhibitive environment of β-cell granules may lead to the accumulation of toxic IAPP aggregates, causing β-cell death in T2D. The cellular environment of beta-cell granules is unique in its high concentrations of Zn2+, insulin and proinsulin c-peptide. Combining discrete molecular dynamics simulations with experimental characterizations and validations, we have investigated both the effects of individual molecules and also their cooperative effects on IAPP aggregation. For example, insulin inhibits IAPP aggregation by competing for the amyloid core around residues 22-29 with its B-chain[2]. Depending on relative concentrations, zinc either promotes or inhibits IAPP aggregation by changing distributions of zinc-coordinated IAPP oligomers with distinct aggregation propensities[3]. Zinc and C-peptide synergistically inhibits IAPP aggregation by stabilizing IAPP in an aggregation-incompetent state upon the formation of zinc-coordinated molecular complex with C-peptide[4]. These mechanistic insights to the endogenous inhibition of IAPP aggregation may help design novel therapeutic strategies that either mimic or promote the native inhibition of IAPP aggregation.