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His18 promotes reactive oxidative stress production in copper-ion mediated human islet amyloid polypeptide aggregation.

ABSTRACT: Copper ions play a critical role in human islet amyloid polypeptide (hIAPP) aggregation, which has been found in more than 90% of patients with type-2 diabetes (T2D). The role of Cu(ii) in the cell cytotoxicity with hIAPP has been explored in two aspects: inhibiting the formation of fibrillar structures and stimulating the generation of reactive oxygen species (ROS). In this work, we carried out spectroscopic studies of Cu(ii) interacting with several hIAPP fragments and their variants as well. Electron paramagnetic resonance (EPR) measurements and Amplex Red analysis showed that the amount of H₂O₂ generated in hIAPP(11-28) solution co-incubated with Cu(ii) was remarkably more than hIAPP(1-11) and hIAPP(28-37). Furthermore, the H₂O₂ level was seriously reduced when His18 of hIAPP(11-28) was replaced by Arg(R) or Ser(S), indicating that His18 is the key residue of Cu(ii) binding to hIAPP(11-28) to promote H₂O₂ generation. This is likely because the donation of electrons from the peptide to Cu(ii) ions would result in the formation of the redox-active complexes, which could stimulate the formation of H₂O₂. Overall, this study provides further insight into the molecular mechanism of Cu(ii) induced ROS generation.

SUBMITTER: Huo G

PROVIDER: S-EPMC9049296 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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His18 promotes reactive oxidative stress production in copper-ion mediated human islet amyloid polypeptide aggregation.

Huo Gengyang G Chen Wenyong W Wang Jianhua J Chu Xinxing X Xu Wei W Li Bin B Zhang Yi Y Xu Binqian B Zhou Xingfei X

RSC advances 20200204 10

Copper ions play a critical role in human islet amyloid polypeptide (hIAPP) aggregation, which has been found in more than 90% of patients with type-2 diabetes (T2D). The role of Cu(ii) in the cell cytotoxicity with hIAPP has been explored in two aspects: inhibiting the formation of fibrillar structures and stimulating the generation of reactive oxygen species (ROS). In this work, we carried out spectroscopic studies of Cu(ii) interacting with several hIAPP fragments and their variants as well. ...[more]

PMID: 35497413

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Project description:Amyloid diseases are degenerative pathologies, highly prevalent today because they are closely related to aging, that have in common the erroneous folding of intrinsically disordered proteins (IDPs) which aggregate and lead to cell death. Type 2 Diabetes involves a peptide called human islet amyloid polypeptide (hIAPP), which undergoes a conformational change, triggering the aggregation process leading to amyloid aggregates and fibers rich in β-sheets mainly found in the pancreas of all diabetic patients. Inhibiting the aggregation of amyloid proteins has emerged as a relevant therapeutic approach and we have recently developed the design of acyclic flexible hairpins based on peptidic recognition sequences of the amyloid β peptide (Aβ1-42) as a successful strategy to inhibit its aggregation involved in Alzheimer's disease. The present work reports the extension of our strategy to hIAPP aggregation inhibitors. The design, synthesis, conformational analyses, and biophysical evaluations of dynamic β-hairpin like structures built on a piperidine-pyrrolidine β-turn inducer are described. By linking to this β-turn inducer three different arms (i) pentapeptide, (ii) tripeptide, and (iii) α/aza/aza/pseudotripeptide, we demonstrate that the careful selection of the peptide-based arms from the sequence of hIAPP allowed to selectively modulate its aggregation, while the peptide character can be decreased. Biophysical assays combining, Thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis, and mass spectrometry showed that the designed compounds inhibit both the oligomerization and the fibrillization of hIAPP. They are also capable to decrease the aggregation process in the presence of membrane models and to strongly delay the membrane-leakage induced by hIAPP. More generally, this work provides the proof of concept that our rational design is a versatile and relevant strategy for developing efficient and selective inhibitors of aggregation of amyloidogenic proteins.

Dataset Information

His18 promotes reactive oxidative stress production in copper-ion mediated human islet amyloid polypeptide aggregation.

Publications

His18 promotes reactive oxidative stress production in copper-ion mediated human islet amyloid polypeptide aggregation.

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