Human zinc binding cysteine proteome

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 Zn2+ binding remain undefined. Here we develop ZnCPT, a deep and quantitative mapping of the zinc binding cysteine proteome. We define 6173 zinc binding protein cysteines, uncovering protein families across major domains of biology that are subject to either constitutive or inducible zinc binding. 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 binding, 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 of protein function.