美国丹娜-法伯癌症研究所Edward T. Chouchani小组绘制了人类锌结合半胱氨酸蛋白质组。相关论文于2024年12月31日在线发表在《细胞》杂志上。

研究人员开发了ZnCPT，一个深度且定量的锌结合半胱氨酸蛋白质组图谱。研究人员定义了6173个锌结合半胱氨酸，揭示了跨越生物学主要领域的蛋白质家族，这些蛋白质家族受到持续性或诱导性锌结合的影响。ZnCPT使得系统性地发现锌调控的结构、酶活性和别构功能域成为可能。

在此基础上，研究人员识别了52个受锌结合影响的癌症遗传依赖性，并提出了对锌诱导细胞毒性敏感的恶性肿瘤。研究人员发现了锌调控谷胱甘肽还原酶（GSR）的机制，该机制在GSR依赖性的肺癌中驱动细胞死亡。研究人员提供了ZnCPT作为理解锌调控蛋白质功能机制的资源。

据了解，锌是一个重要的微量营养素，调节着广泛的生理过程，通常通过锌与蛋白质半胱氨酸残基的结合发挥作用。尽管锌在调节蛋白质功能中至关重要，但在人类蛋白质组中，大多数受锌结合调控的半胱氨酸位点仍未被定义。

附：英文原文

Title: The human zinc-binding cysteine proteome

Author: Nils Burger, Melanie J. Mittenbühler, Haopeng Xiao, Sanghee Shin, Shelley M. Wei, Erik K. Henze, Sebastian Schindler, Sepideh Mehravar, David M. Wood, Jonathan J. Petrocelli, Yizhi Sun, Hans-Georg Sprenger, Pedro Latorre-Muro, Amanda L. Smythers, Luiz H.M. Bozi, Narek Darabedian, Yingde Zhu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Jianwei Che, Edward T. Chouchani

Issue&Volume: 2024-12-31

Abstract: 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.

DOI: 10.1016/j.cell.2024.11.025

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01341-2