CE44 - Biochimie du Vivant

Role of molecular CHAPerones During COPper Stress in bacteria – ChapCop

Submission summary

Prokaryotes have evolved sophisticated strategies to regulate intra-cellular copper concentration since it is essential for cell survival to import copper and incorporate it at the active site of key enzymes, but a higher intra-cellular concentration is toxic. These copper-concentration regulation mechanisms can be insufficient in environments with high amount of copper, leading to cell death. This bactericidal property of copper has been exploited since the Middle Age and regains interest nowadays to substitute antibiotics. Besides, copper is also used by the immune system to eliminate pathogenic organisms. Nevertheless, how copper or copper complexes induces cell death is not understood. The ChapCop project aims at a better understanding at both the cellular and the molecular levels of the mechanisms responsible for copper-induced toxicity and the resistance strategies implemented by bacteria to resist to copper stress.
This project is based on our recent preliminary results showing (i) that a high concentration of copper induces the denaturation of the stable structures of many proteins leading to the formation of protein aggregates and (ii) that some molecular chaperones are able to decrease copper-induced protein aggregation. Our working hypotheses is that molecular chaperones with structural zinc sites may play a major role in bacterial survival. Copper is likely to damage these zinc sites, leading to a structural transition enabling chaperone activation against copper-induced aggregation.
Using Escherichia coli as a model, two main objectives will be pursued. 1- The relative impact of free copper or of various copper-complexes known for their anti-bacterial activities on protein aggregation will be determined. Copper-sensitive proteins that tend to aggregate under a variety of conditions will be identified as well as copper complexes with the most potent bactericidal effect. 2- The role of holdase chaperones in condition of copper stress will be assessed in vivo and in vitro on model proteins as well as on physiological clients, with a special focus on the Zn-containing holdases chaperones Hsp33 and DnaJ.
The ChapCop project gathers five partners with complementary expertise in copper handling, (bio)chemical reactivity, proteostasis, and molecular chaperones. Our interdisciplinary approach relying on bioinorganic chemistry, microbiology, biochemistry and structural biology will provide major breakthroughs on the understanding of strategies dedicated to maintaining bacterial proteome integrity during toxic copper exposure and per se, will define the bacterial strategies to survive to copper-stress.

Project coordination

Marianne Ilbert (Laboratoire de Bioenergetique et d'ingenierie des Proteines)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

BIP02 Bioénergétique et ingénierie des protéines
LCBM LABORATOIRE DE CHIMIE ET BIOLOGIE DES MÉTAUX
IC _UNISTRA Institut de Chimie de Strasbourg (UMR 7177)
LMGM LABORATOIRE DE MICROBIOLOGIE ET GENETIQUE MOLECULAIRES
BIP01 Laboratoire de Bioenergetique et d'ingenierie des Proteines

Help of the ANR 548,415 euros
Beginning and duration of the scientific project: October 2019 - 48 Months

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