Copper-induced cytotoxicity: reactive oxygen species or islet amyloid polypeptide oligomer formation

Yu, Yingchun; Lei, Peng; Hu, Jia; Wu, Wei-Hui; Zhao, Yufen; Li, Yanmei

doi:10.1039/c0cc02141e

Cited by 63 publications

(85 citation statements)

References 20 publications

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“…Indeed, the minimum near 200 nm undergoes a red shift over time which indicates a stabilization of an α-helix conformation, while there is not the presence of the negative peak at 216 nm over time, confirming the absence of β-sheet structures. 46 Therefore, although copper induces a conformational change onto the h-amylin molecule which shifts the equilibrium toward a more structured form (see MS results), the lack of β-sheet structures as seen by CD indicates the absence of an induced fibrillar form of the protein. This result was further confirmed by ThT fluorescence measurements.…”

Section: Resultsmentioning

confidence: 96%

“…Indeed, copper(II) induces a conformational change on the protein that, although is in a more structured state (H/D exchange MS and CD results), is less prone to aggregation, in accordance with previous works. 23,46 Finally, in order to get a closer insight onto the mechanism by which copper(II) induces the above reported changes on both the conformation and aggregation properties of h-amylin, we have used the 17-29 h-amylin fragment (Figure 3) in order to carry out simulations as well as solid-state NMR measurements on the aggregated state. The reason and the validity of using this particular peptide portion has already been reported elsewhere.…”

Section: Resultsmentioning

confidence: 99%

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The role of copper(ii) in the aggregation of human amylin

Sinopoli

Magrı̀²,

Milardi³

et al. 2014

Metallomics

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Amylin is the 37-residue peptide hormone produced by the islet β-cells in the pancreas and the formation of amylin aggregates is strongly associated with β-cells degeneration in type 2 diabetes, as demonstrated by more than 95% of patients exhibiting amylin amyloid upon autopsy.It is widely recognized that metal ions such as copper(II) have been implicated in the aggregation process of amyloidogenic peptides such as Aβ and α-synuclein and there is evidence that also amylin self-assembly is largely affected by copper(II). For this reason, in this work, the role of copper(II) in the aggregation of amylin has been investigated by several different experimental approaches. Mass spectrometric investigations show that copper(II) induces significant changes in the amylin structure which decrease the protein fibrillogenesis as observed by ThT measurements. Accordingly, solid-state NMR experiments together with computational analysis carried out on a model amylin fragment confirmed the non fibrillogenic nature of the copper(II) induced aggregated structure. Finally, the presence of copper(II) is also shown to have a major influence on amylin proneness to be degraded by proteases and cytotoxicity studies on different cell cultures are reported.4

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

The role of copper(ii) in the aggregation of human amylin

Sinopoli

Magrı̀²,

Milardi³

et al. 2014

Metallomics

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“…[20] Binding of metal ions (e.g., Cu II , Zn II ) to peptides is shown to accelerate amyloidogenic peptide aggregation or induce the formation and stabilization of toxic oligomeric aggregates. [1b,20b,c,21] Upon the formation of 2-oxo-histidine, metal binding affinities were reported to be substantially decreased; thus, oxidative modifications of histidine residues might destabilize complexes of amyloidogenic peptides with metal ions. [20e,22] Collectively, methionine, histidine, and/or tyrosine residues, the potential oxidation sites of Aβ, α-Syn, or hIAPP, which were suggested to be essential for the properties and aggregation of these amyloidogenic peptides, were indicated by our MS and NMR studies.…”

Section: Resultsmentioning

confidence: 99%

An Iridium(III) Complex as a Photoactivatable Tool for Oxidation of Amyloidogenic Peptides with Subsequent Modulation of Peptide Aggregation

Kang

Lee

Nam

et al. 2017

Chemistry A European J

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Aggregates of amyloidogenic peptides are involved in the pathogenesis of several degenerative disorders. Herein, an iridium(III) complex, Ir-1, is reported as a chemical tool for oxidizing amyloidogenic peptides upon photoactivation and subsequently modulating their aggregation pathways. Ir-1 was rationally designed based on multiple characteristics, including 1) photoproperties leading to excitation by low-energy radiation; 2) generation of reactive oxygen species responsible for peptide oxidation upon photoactivation under mild conditions; and 3) relatively easy incorporation of a ligand on the IrIII center for specific interactions with amyloidogenic peptides. Biochemical and biophysical investigations illuminate that the oxidation of representative amyloidogenic peptides (i.e., amyloid-β, α-synuclein, and human islet amyloid polypeptide) is promoted by light-activated Ir-1, which alters the conformations and aggregation pathways of the peptides. Additionally, their potential oxidation sites are identified as methionine, histidine, or tyrosine residues. Overall, our studies on Ir-1 demonstrate the feasibility of devising metal complexes as chemical tools suitable for elucidating the nature of amyloidogenic peptides at the molecular level, as well as controlling their aggregation.

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“…The ThT fluorescence assay was prepared by mixing 10 L [25]. Before the aggregation, A1-42 (American Peptide Company, INC., USA) was solubilized in hexafluoroisopropanol at 1 mM to avoid any pre-existing aggregates.…”

Section: Tht Fluorescence Assaymentioning

confidence: 99%

Exploring the binding mechanism of thioflavin-T to the β-amyloid peptide by blind docking method

et al. 2011

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Using blind dock method, we find that thioflavin-T (ThT) can bind to both monomers and fibrils of the full-length β-amyloid peptide (A1-42) and has a higher binding affinity to the fibrils. It is shown that the hydrophobic interaction between the ligand (ThT) and substrate (A1-42) are stronger than hydrogen bonds. Furthermore, ThT tends to be located near the C-terminus of A monomer through hydrophobic and electrostatic interactions, while it tends to contact the residues Met35 and Gly27 of the fibril surface mainly through hydrophobic interaction. Finally, according to the docking results and ThT fluorescence assay, a kinetic equation is proposed to deduce the aggregation rate coefficient of A1-42.

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Copper-induced cytotoxicity: reactive oxygen species or islet amyloid polypeptide oligomer formation

Cited by 63 publications

References 20 publications

The role of copper(ii) in the aggregation of human amylin

The role of copper(ii) in the aggregation of human amylin

An Iridium(III) Complex as a Photoactivatable Tool for Oxidation of Amyloidogenic Peptides with Subsequent Modulation of Peptide Aggregation

Exploring the binding mechanism of thioflavin-T to the β-amyloid peptide by blind docking method

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