Quantitative interactome analysis reveals a chemoresistant edgotype.
Quantitative interactome analysis reveals a chemoresistant edgotype.
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DOI：
10.1038/ncomms8928
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发表时间：
2015-08-03
影响因子：
16.6
通讯作者：
Bruce JE
中科院分区：
文献类型：
--
作者：
Chavez JD;Schweppe DK;Eng JK;Zheng C;Taipale A;Zhang Y;Takara K;Bruce JE
化疗耐药是许多癌症治疗失败的常见模式。肿瘤通过多种机制产生对化疗药物的耐药性，其中蛋白质起着关键作用。蛋白质构象和相互作用的变化影响细胞对环境条件的反应，从而促进新表型的发展。了解蛋白质相互作用网络如何适应产生新功能或改变表型的能力受到无法确定蛋白质组学规模上结构和蛋白质相互作用变化的限制。在这里，化学交联和质谱被用来量化在多药耐药的人癌细胞的蛋白质结构和相互作用的变化。定量分析由1391个交联肽组成的最大的交联衍生的蛋白质相互作用网络，允许在化学耐药细胞模型中进行“edgotype”分析。我们检测到蛋白质相互作用和结构的一致变化，包括涉及细胞角蛋白、拓扑异构酶-2- α和翻译后修饰组蛋白的变化，这些变化与化学耐药表型相关。蛋白质-蛋白质相互作用的改变导致细胞表型的改变。在这里，作者使用交联质谱法在药物敏感和耐药的HeLa细胞中获得了定量的蛋白质相互作用网络，并发现了一种耐药的“edgotype”。
Chemoresistance is a common mode of therapy failure for many cancers. Tumours develop resistance to chemotherapeutics through a variety of mechanisms, with proteins serving pivotal roles. Changes in protein conformations and interactions affect the cellular response to environmental conditions contributing to the development of new phenotypes. The ability to understand how protein interaction networks adapt to yield new function or alter phenotype is limited by the inability to determine structural and protein interaction changes on a proteomic scale. Here, chemical crosslinking and mass spectrometry were employed to quantify changes in protein structures and interactions in multidrug-resistant human carcinoma cells. Quantitative analysis of the largest crosslinking-derived, protein interaction network comprising 1,391 crosslinked peptides allows for ‘edgotype' analysis in a cell model of chemoresistance. We detect consistent changes to protein interactions and structures, including those involving cytokeratins, topoisomerase-2-alpha, and post-translationally modified histones, which correlate with a chemoresistant phenotype. Changes in protein–protein interactions result in changes to cellular phenotype. Here the authors use crosslinking mass spectrometry to derive a quantitative protein interaction network in drug-sensitive and -resistant HeLa cells, and uncover a chemoresistant ‘edgotype'.