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Quantifying the Binding Interactions Between CuII and Peptide Residues in the Presence and Absence of Chromophores
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Copper(II) ions affect the gating dynamics of the 20S proteasome: a molecular and in cell study

Anna Maria Santoro1, Irene Monaco1,2, Francesco Attanasio1

  • 1Istituto di Biostrutture e Bioimmagini - CNR Sede di Catania, Via P. Gaifami, 9- 95126 Catania, Italy.

Scientific Reports
|September 17, 2016
PubMed

Insights

Copper (II) ions inhibit proteasome activity in cancer cells by altering its structure and function. This proteasome inhibition, alongside ROS generation, presents a potential anticancer strategy.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • Cancer cells exhibit altered metabolism, increasing sensitivity to proteasome inhibition and copper levels.
  • Copper complexes with proteasome inhibition capabilities are a promising anticancer strategy.
  • The precise mechanism of copper-mediated proteasome inhibition remains largely unelucidated.

Purpose of the Study:

  • To investigate the mechanism by which copper (II) ions inhibit proteasome activity.
  • To explore the effects of copper (II) on isolated 20S proteasomes and in cancer cells.

Main Methods:

  • Inhibition assays using isolated 20S proteasomes.
  • Analysis of copper (II) effects on proteasome conformation and assembly.
  • Assessment of proteasome activity in HeLa cells cultured in copper (II)-supplemented media.
  • Evaluation of antioxidant effects on copper (II)-induced cellular responses.

Main Results:

  • Copper (II) ions inhibit all three peptidase activities of isolated 20S proteasomes (IC50 in micromolar range).
  • Copper (II) does not induce redox reactions or disrupt 20S proteasome assembly but causes conformational changes affecting channel gating.
  • Proteasome activity decreased in HeLa cells with copper (II) supplementation, an effect partially mitigated by antioxidants.
  • Copper (II) induces ROS-mediated proteasome flooding and 26S proteasome disassembly in cancer cells.

Conclusions:

  • Copper (II) inhibition of 20S proteasome activity involves conformational changes favoring a closed state.
  • The anticancer effect of copper (II) in cancer cells results from multiple events, including ROS generation and proteasome disassembly.
  • Copper (II) ions represent a potential therapeutic agent targeting proteasome function in cancer.

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