Copper(II) ions affect the gating dynamics of the 20S proteasome: a molecular and in cell study(283 views visite) Santoro AM, Monaco I, Attanasio F, Lanza V, Pappalardo G, Tomasello MF, Cunsolo A, Rizzarelli E, De Luigi A, Salmona M, Milardi D
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Affiliations Affiliazioni: *** IBB - CNR ***
Istituto di Biostrutture e Bioimmagini - CNR Sede di Catania, Via P. Gaifami, 9- 95126 Catania, Italy., Fondazione RiMed, Via Bandiera 11, 90133, Palermo, Italy., Dipartimento di Scienze Chimiche, Universita di Catania, Viale Andrea Doria 6, 95125 Catania, Italy., IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via Giuseppe La Masa 19, 20156, Milano, Italy.,
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Copper(II) ions affect the gating dynamics of the 20S proteasome: a molecular and in cell study
Due to their altered metabolism cancer cells are more sensitive to proteasome inhibition or changes of copper levels than normal cells. Thus, the development of copper complexes endowed with proteasome inhibition features has emerged as a promising anticancer strategy. However, limited information is available about the exact mechanism by which copper inhibits proteasome. Here we show that Cu(II) ions simultaneously inhibit the three peptidase activities of isolated 20S proteasomes with potencies (IC50) in the micromolar range. Cu(II) ions, in cell-free conditions, neither catalyze red-ox reactions nor disrupt the assembly of the 20S proteasome but, rather, promote conformational changes associated to impaired channel gating. Notably, HeLa cells grown in a Cu(II)-supplemented medium exhibit decreased proteasome activity. This effect, however, was attenuated in the presence of an antioxidant. Our results suggest that if, on one hand, Cu(II)-inhibited 20S activities may be associated to conformational changes that favor the closed state of the core particle, on the other hand the complex effect induced by Cu(II) ions in cancer cells is the result of several concurring events including ROS-mediated proteasome flooding, and disassembly of the 26S proteasome into its 20S and 19S components.
Copper(II) ions affect the gating dynamics of the 20S proteasome: a molecular and in cell study
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