Copper(I)-nitrene platform for chemoproteomic profiling of methionine

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2024-05-18 DOI:10.1038/s41467-024-48403-0

Samrat Sahu, Benjamin Emenike, Christian Michel Beusch, Pritha Bagchi, David Ezra Gordon, Monika Raj

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Abstract

Methionine plays a critical role in various biological and cell regulatory processes, making its chemoproteomic profiling indispensable for exploring its functions and potential in protein therapeutics. Building on the principle of rapid oxidation of methionine, we report Copper(I)-Nitrene Platform for robust, and selective labeling of methionine to generate stable sulfonyl sulfimide conjugates under physiological conditions. We demonstrate the versatility of this platform to label methionine in bioactive peptides, intact proteins (6.5-79.5 kDa), and proteins in complex cell lysate mixtures with varying payloads. We discover ligandable proteins and sites harboring hyperreactive methionine within the human proteome. Furthermore, this has been utilized to profile oxidation-sensitive methionine residues, which might increase our understanding of the protective role of methionine in diseases associated with elevated levels of reactive oxygen species. The Copper(I)-Nitrene Platform allows labeling methionine residues in live cancer cells, observing minimal cytotoxic effects and achieving dose-dependent labeling. Confocal imaging further reveals the spatial distribution of modified proteins within the cell membrane, cytoplasm, and nucleus, underscoring the platform’s potential in profiling the cellular interactome.

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用于蛋氨酸化学蛋白质组分析的铜（I）-芘平台

蛋氨酸在各种生物和细胞调控过程中发挥着关键作用，因此对其进行化学蛋白质组学分析对于探索其在蛋白质治疗中的功能和潜力不可或缺。基于蛋氨酸快速氧化的原理，我们报告了铜(I)-芘平台，该平台可在生理条件下对蛋氨酸进行稳健的选择性标记，生成稳定的磺酰亚胺轭合物。我们展示了该平台的多功能性，可标记生物活性肽、完整蛋白质（6.5-79.5 kDa）和复杂细胞裂解物混合物中不同有效载荷的蛋白质中的蛋氨酸。我们在人类蛋白质组中发现了可配体蛋白质和含有高反应蛋氨酸的位点。此外，我们还利用这种方法剖析了对氧化敏感的蛋氨酸残基，这可能会加深我们对蛋氨酸在与活性氧水平升高有关的疾病中的保护作用的了解。铜（I）-芘平台可以标记活癌细胞中的蛋氨酸残基，观察到最小的细胞毒性效应，并实现剂量依赖性标记。共焦成像进一步揭示了细胞膜、细胞质和细胞核内修饰蛋白质的空间分布，凸显了该平台在剖析细胞相互作用组方面的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.