Zinc-Induced Conformational Transitions in Human Islet Amyloid Polypeptide and Their Role in the Inhibition of Amyloidosis

Abstract

Type-2 diabetes mellitus (T2DM) is a disease hallmarked by improper homeostasis within the islets of Langerhans of the pancreas. The most critical species affected is insulin, which is produced by the β-cells of the islets, but there are a number of other species copackaged and cosecreted within the insulin granules. This includes zinc, which exists in high (millimolar) concentrations within the β-cells, and islet amyloid polypeptide (IAPP), which is an amyloid peptide thought to induce β-cell apoptosis through self-association into toxic amyloid oligomers. Zinc is essential in the packaging of crystalline insulin within the vesicles but it can also bind and interact with IAPP. This implies a complex relationship between all three species and diabetes, particularly in the structure and function of toxic IAPP aggregates. Atypical (low or high) concentrations of zinc generally appear to correlate with increased hIAPP aggregation, whereas physiological zinc concentrations have an inhibitory effect. To better understand how zinc ions alter the monomer and oligomer structure of hIAPP in vitro, we employ a combination of ion mobility mass spectrometry and atomic force microscopy. We observe an increase in the extended β-hairpin conformation of hIAPP when it is bound to zinc. With sufficiently low concentrations of zinc this could result in an association site for zinc-free hIAPP, promoting amyloid aggregation. At high zinc concentrations, we see the appearance of a secondary zinc association site whose coordination could account for the loss of inhibition at high zinc concentrations. Generally, it appears that zinc preferentially stabilizes the β-hairpin conformation of hIAPP and the population of zinc-bound hIAPP in solution determines what effect this has on amyloid aggregation.

Zinc Interactions with a Soluble Mutated Rat Amylin to Mimic Whole Human Amylin: An Experimental and Simulation Approach to Understand Stoichiometry, Speciation and Coordination of the Metal Complexes

“…The same behavior was observed for HA and QB protons of K1 residue. TOCSY and HSQC spectra related to the aliphatic region (Figure ) clearly showed the shift of the spin system of the HA proton of Lys1 residue, whereas in the aromatic region (Figure ) a shift of the signals related to the H ϵ 1 and Hδ2 protons from the imidazole ring of His18 residue occurred …”

“…TOCSY and HSQC spectra relatedt ot he aliphatic region ( Figure 9) clearly showedt he shift of the spin system of the HA protono fL ys1 residue, whereas in the aromatic region ( Figure 8) as hift of the signals relatedt ot he He1a nd Hd2p rotons from the imidazole ring of His18 residue occurred. [70,71] At pH 7.15, ac omparison between 1D spectra of Zn-r-IAPP(1-37;R18 H) system and the spectra of apo-peptide shows only little shifts of the signals of aromatic imidazole protons of His18 residue. This effect was also evident in the aromatic region of TOCSY spectrum.…”

Amyloids: Regulators of Metal Homeostasis in the Synapse

“…Similar biphasic effects of Zn 2+ is observed also in T2DM. Zn 2+ , which is co-secreted with insulin and IAPP from the pancreatic β cells, has a dual effect on the aggregation and cell toxicity of IAPP in a concentration-dependent manner [161]. Zn 2+ at the physiological concentration inhibits the aggregation of IAPP, meanwhile, atypical (low or high) concentrations of Zn 2+ enhance the aggregation.…”

α-CGRP disrupts amylin fibrillization and regulates insulin secretion: implications on diabetes and migraine

“…[53][54][55] In IMS-MS, oligomers are identied via orthogonal mass to charge (m/z) and dri time dimensions; the latter can yield valuable structural information. Amylin has been extensively studied with IMS-MS, 30,[56][57][58][59][60] and the main focus lies on structures of the monomers and dimers. 30,57,58,60 Here, in addition to traditional IMS-MS analysis of amylin and CGRP homoand hetero-oligomers in solution, we perform liquid chromatography (LC)-IMS-MS of single mouse islets incubated with each peptide or their mixture to evaluate their synergistic effect on insulin secretion.…”

“…Amylin has been extensively studied with IMS-MS, 30,[56][57][58][59][60] and the main focus lies on structures of the monomers and dimers. 30,57,58,60 Here, in addition to traditional IMS-MS analysis of amylin and CGRP homoand hetero-oligomers in solution, we perform liquid chromatography (LC)-IMS-MS of single mouse islets incubated with each peptide or their mixture to evaluate their synergistic effect on insulin secretion. This work is further complemented by atomistic replica exchange molecular dynamics (REMD) simulations, transmission electron microscopy (TEM), and through evaluating multiple pathways of toxicity using cultured mouse b-cells.…”