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COPPER INDUCES PROTEIN AGGREGATION, A TOXIC PROCESS COMPENSATED BY MOLECULAR CHAPERONES.

ABSTRACT: Copper is a powerful antimicrobial and antiviral agent, which has interest through several biomedical applications. Nevertheless, how copper induces the cellular damage is not fully understood. Two main mechanisms are claimed to be involved, i.e. Cu catalyzed reactive oxygen species production (ROS) and replacements of other essential metal ions, such as Fe in Fe-S clusters by Cu. In the present work, we cumulate strong evidence for the importance of a third mechanism, which proposes that Cu damaging effects are due to its ability to cause massive protein aggregation in a ROS independent mechanism. We further show that Hsp33, a redox-regulated molecular chaperone in Escherichia coli, can prevent Cu-induced protein aggregation, suggesting an important role of the chaperoning system in defense against Cu-toxicity. A closer inspection of the mechanism of how Cu can activate Hsp33 revealed two intriguing features, i) a redox-state specificity of Cu+ vs Cu2+, and ii) an unprecedented mechanism of Hsp33-activation via a non-redox trans-metalation. Indeed, our data suggest that two Cu+ bind to the Zn-Cys4-finger site in Hsp33, which lead to a replacement of one Zn2+ by two Cu+ without Cys oxidation. In contrast, Cu2+ oxidizes the Cys in the Zn-finger, analogue to other oxidative stress effectors of Hsp33. Hence, the present results give several new insights in the antimicrobial mechanism of Cu and how bacteria defend against it.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Escherichia Coli

SUBMITTER: Rosi Fassler

LAB HEAD: Dana Reichmann

PROVIDER: PXD019288 | Pride | 2022-02-10

REPOSITORIES: Pride

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