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.
Show 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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