A comprehensive landscape of the zinc-regulated human proteome

Burger, N.; Mittenbuhler, M.; Xiao, H.; Shin, S.; Bozi, L.; Wei, S.; Sprenger, H.-G.; Sun, Y.; Zhu, Y.; Darabedian, N.; Petrocelli, J.; Latorre Muro, P.; Che, J.; Chouchani, E. T.

doi:10.1101/2024.01.04.574225

bioRxiv · 10.1101/2024.01.04.574225

A comprehensive landscape of the zinc-regulated human proteome

Burger, N.·Mittenbuhler, M.·Xiao, H.·Shin, S.·Bozi, L.·Wei, S.·Sprenger, H.-G.·Sun, Y.·Zhu, Y.·Darabedian, N.·Petrocelli, J.·Latorre Muro, P.·Che, J.·Chouchani, E. T.

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Abstract

Zinc is an essential micronutrient that regulates a wide range of physiological processes, principally through Zn2+ binding to protein cysteine residues. Despite being critical for modulation of protein function, for the vast majority of the human proteome the cysteine sites subject to regulation by Zn2+ binding remain undefined. Here we develop ZnCPT, a comprehensive and quantitative mapping of the zinc-regulated cysteine proteome. We define 4807 zinc-regulated protein cysteines, uncovering protein families across major domains of biology that are subject to either constitutive or inducible modification by zinc. ZnCPT enables systematic discovery of zinc-regulated structural, enzymatic, and allosteric functional domains. On this basis, we identify 52 cancer genetic dependencies subject to zinc regulation, and nominate malignancies sensitive to zinc-induced cytotoxicity. In doing so, we discover a mechanism of zinc regulation over Glutathione Reductase (GSR) that drives cell death in GSR-dependent lung cancers. We provide ZnCPT as a resource for understanding mechanisms of zinc regulation over protein function.

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Burger, N., Mittenbuhler, M., Xiao, H., Shin, S., Bozi, L., Wei, S., Sprenger, H.-G., Sun, Y., Zhu, Y., Darabedian, N., Petrocelli, J., Latorre Muro, P., Che, J., Chouchani, E. T.. 2024-01-05. A comprehensive landscape of the zinc-regulated human proteome. https://doi.org/10.1101/2024.01.04.574225

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