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).

中文翻译：

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化学蛋白质组学分析绘制锌依赖性半胱氨酸反应性

作为一种重要的微量营养素，锌是多种蛋白质的结构、功能和信号网络不可或缺的一部分。由于摄入过量或缺乏而导致的锌水平失调与一系列健康疾病有关。在这种背景下，在分子水平上了解锌调节的生物过程与公共卫生和临床实践具有重要意义。然而，识别和表征不同蛋白质形式的锌调节蛋白仍然是推进锌生物学的一项艰巨任务。在此，我们通过开发定量化学蛋白质组学平台来应对这一挑战，该平台可全面分析细胞锌耗尽后蛋白质半胱氨酸的反应性。利用蛋白质缀合树脂从培养基中选择性去除 Zn ²⁺，我们根据锌耗尽时反应性的增加，鉴定了具有多种功能的蛋白质上的一系列锌敏感半胱氨酸。值得注意的是，我们发现锌调节选定靶蛋白的酶活性、翻译后修饰和亚细胞分布，例如过氧化还原蛋白 6 (PRDX6)、血小板活化因子乙酰水解酶 IB 亚基 α1 (PAFAH1B3) 和磷酸甘油酸激酶 (PGK1)。