Chemoproteomic Profiling Maps Zinc-Dependent Cysteine Reactivity

• Published in: Chemical research in toxicology 2024-04, Vol.37 (4), p.620-632
• Main Authors: Qiu, Nan, Pechalrieu, Dany, Abegg, Daniel, Adibekian, Alexander
• Format: Article
• Language: English
• Subjects: Cysteine - chemistry; Proteins - chemistry; Zinc - metabolism
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/acs.chemrestox.3c00416

As a vital micronutrient, zinc is integral to the structure, function, and signaling networks of diverse proteins. Dysregulated zinc levels, due to either excess intake or deficiency, are associated with a spectrum of health disorders. In this context, understanding zinc-regulated biological processes at the molecular level holds significant relevance to public health and clinical practice. Identifying and characterizing zinc-regulated proteins in their diverse proteoforms, however, remain a difficult task in advancing zinc biology. Herein, we address this challenge by developing a quantitative chemical proteomics platform that globally profiles the reactivities of proteinaceous cysteines upon cellular zinc depletion. Exploiting a protein-conjugated resin for the selective removal of Zn2+ from culture media, we identify an array of zinc-sensitive cysteines on proteins with diverse functions based on their increased reactivity upon zinc depletion. Notably, we find that zinc regulates the enzymatic activities, post-translational modifications, and subcellular distributions of selected target proteins such as peroxiredoxin 6 (PRDX6), platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3), and phosphoglycerate kinase (PGK1).