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Discovery of metal-binding proteins by thermal proteome profiling
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2024-02-26 , DOI: 10.1038/s41589-024-01563-y
Xin Zeng , Tiantian Wei , Xianghe Wang , Yuan Liu , Zhenshu Tan , Yihai Zhang , Tianyu Feng , Yao Cheng , Fengzhang Wang , Bin Ma , Wei Qin , Chuanping Gao , Junyu Xiao , Chu Wang

Metal-binding proteins (MBPs) have various and important biological roles in all living species and many human diseases are intricately linked to dysfunctional MBPs. Here, we report a chemoproteomic method named ‘metal extraction-triggered agitation logged by thermal proteome profiling’ (METAL-TPP) to globally profile MBPs in proteomes. The method involves the extraction of metals from MBPs using chelators and monitoring the resulting protein stability changes through thermal proteome profiling. Applying METAL-TPP to the human proteome with a broad-spectrum chelator, EDTA, revealed a group of proteins with reduced thermal stability that contained both previously known MBPs and currently unannotated MBP candidates. Biochemical characterization of one potential target, glutamine-fructose-6-phosphate transaminase 2 (GFPT2), showed that zinc bound the protein, inhibited its enzymatic activity and modulated the hexosamine biosynthesis pathway. METAL-TPP profiling with another chelator, TPEN, uncovered additional MBPs in proteomes. Collectively, this study developed a robust tool for proteomic discovery of MBPs and provides a rich resource for functional studies of metals in cell biology.



中文翻译:

通过热蛋白质组分析发现金属结合蛋白

金属结合蛋白 (MBP) 在所有生物物种中具有多种重要的生物学作用,许多人类疾病与功能失调的 MBP 密切相关。在这里,我们报告了一种名为“热蛋白质组分析记录的金属提取触发搅拌”(METAL-TPP)的化学蛋白质组学方法,用于对蛋白质组中的 MBP 进行全局分析。该方法涉及使用螯合剂从 MBP 中提取金属,并通过热蛋白质组分析监测由此产生的蛋白质稳定性变化。将 METAL-TPP 与广谱螯合剂 EDTA 一起应用于人类蛋白质组,揭示了一组热稳定性降低的蛋白质,其中包含先前已知的 MBP 和目前未注释的 MBP 候选物。一种潜在靶标谷氨酰胺-果糖-6-磷酸转氨酶 2 (GFPT2) 的生化表征表明,锌与该蛋白质结合,抑制其酶活性并调节己糖胺生物合成途径。使用另一种螯合剂 TPEN 进行的 METAL-TPP 分析发现了蛋白质组中的其他 MBP。总的来说,这项研究开发了一种用于 MBP 蛋白质组学发现的强大工具,并为细胞生物学中金属的功能研究提供了丰富的资源。

更新日期:2024-02-26
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