The human zinc-binding cysteine proteome
Zinc is an essential micronutrient that regulates a wide range of physiological processes, most often through zinc binding to protein cysteine residues. Despite being critical for modulation of protein function, the cysteine sites in the majority of the human proteome that are subject to zinc binding remain undefined. Here, we develop ZnCPT, a deep and quantitative mapping of the zinc-binding cysteine proteome. We define 6,173 zinc-binding cysteines, uncovering protein families across major domains of biology that are subject to 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. We discover a mechanism of zinc regulation over glutathione reductase (GSR), which drives cell death in GSR-dependent lung cancers. We provide ZnCPT as a resource for understanding mechanisms of zinc regulation of protein function.
Authors
- Luiz H. M. Bozi (ORCID: https://orcid.org/0000-0002-5698-1181)
- Melanie J. Mittenbühler (ORCID: https://orcid.org/0000-0002-4165-5041)
- Yingde Zhu
- Hans‐Georg Sprenger (ORCID: https://orcid.org/0000-0002-9864-5995)
- Nils Burger (ORCID: https://orcid.org/0000-0003-3227-8894)
- Erik Henze (ORCID: https://orcid.org/0000-0002-7594-4319)
- Sirano Dhe‐Paganon (ORCID: https://orcid.org/0000-0003-0824-5929)
- Edward T. Chouchani (ORCID: https://orcid.org/0000-0002-9776-8790)
- Yizhi Sun (ORCID: https://orcid.org/0000-0001-5911-1117)
- Haopeng Xiao (ORCID: https://orcid.org/0000-0002-4166-647X)
- Sebastian Schindler (ORCID: https://orcid.org/0000-0003-2092-7252)
- Jonathan J. Petrocelli (ORCID: https://orcid.org/0000-0003-1298-4257)
- Hyuk‐Soo Seo (ORCID: https://orcid.org/0000-0003-0646-2102)
- Jianwei Che (ORCID: https://orcid.org/0000-0003-4956-4811)
- Narek Darabedian
- Pedro Latorre‐Muro (ORCID: https://orcid.org/0000-0002-6794-3535)
- David M. Wood (ORCID: https://orcid.org/0000-0002-8275-3510)
- Amanda L. Smythers (ORCID: https://orcid.org/0000-0002-1552-6705)
- Shelley M Wei (ORCID: https://orcid.org/0009-0002-8359-1880)
- Sang-Hee Shin
- Sepideh Mehravar
Institutions
- Cedars-Sinai Medical Center (US)
- Howard Hughes Medical Institute (US)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Cell
- Published
- 2024-12-31
- DOI
- https://doi.org/10.1016/j.cell.2024.11.025
- Citations
- 35
- Primary Topic
- Trace Elements in Health
- Type
- article
- Field-Weighted Citation Impact
- 10.84
Funders
- Howard Hughes Medical Institute
- National Institute on Aging