定量蛋白质组分析揭示了独特的 Hsp90 周期依赖性客户交互作用。

IF 3.3 3区 生物学 Genetics Pub Date : 2024-04-12 DOI:10.1093/genetics/iyae057
Erick I Rios, Davi Gonçalves, Kevin A Morano, Jill L Johnson
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引用次数: 0

摘要

Hsp90 是一种丰富而重要的分子伴侣,它在核苷酸依赖性循环中介导客户蛋白的折叠和激活。由于客户蛋白降解或间接下游效应,Hsp90 抑制会直接或间接影响 10-15% 蛋白的功能。由于其在伴侣致癌蛋白中的作用,Hsp90 是一个重要的药物靶点。然而,占据 ATP 结合袋并能广泛抑制其功能的化合物因其负面作用而尚未得到广泛应用。我们需要更具选择性的抑制剂,但目前还不清楚如何实现选择性抑制。我们对表达野生型 Hsp90 或破坏客户折叠途径不同步骤的突变体的酵母菌株中的可溶性蛋白质进行了定量蛋白质组学分析。在样本集中的 2482 个蛋白质(约占酵母蛋白质的 38%)中,我们观察到其中 350 个蛋白质(14%)的丰度发生了统计学意义上的显著变化(log2 对折变化≥1.5)。其中,257/350(73%)个丰度差异最大的蛋白质以前与 Hsp90 功能有关。对整个数据集进行的主成分分析表明,突变体的影响可分为三个主要群组。作为 Hsp90 突变体影响不同客户池的证据,在不同簇中同时共表达两个突变体可恢复野生型生长。我们的数据表明,Hsp90 能够对多种构象进行采样,这使得伴侣蛋白能够介导多种客户的折叠,而构象灵活性的破坏会导致客户缺陷,这取决于这些状态。
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Quantitative proteomic analysis reveals unique Hsp90 cycle-dependent client interactions.
Hsp90 is an abundant and essential molecular chaperone that mediates the folding and activation of client proteins in a nucleotide-dependent cycle. Hsp90 inhibition directly or indirectly impacts the function of 10-15% of all proteins due to degradation of client proteins or indirect downstream effects. Due to its role in chaperoning oncogenic proteins, Hsp90 is an important drug target. However, compounds that occupy the ATP-binding pocket and broadly inhibit function have not achieved widespread use due to negative effects. More selective inhibitors are needed; however, it is unclear how to achieve selective inhibition. We conducted a quantitative proteomic analysis of soluble proteins in yeast strains expressing wild-type Hsp90 or mutants that disrupt different steps in the client folding pathway. Out of 2,482 proteins in our sample set (approximately 38% of yeast proteins), we observed statistically significant changes in abundance of 350 (14%) of those proteins (log2 fold change ≥1.5). Of these, 257/350 (∼73%) with the strongest differences in abundance were previously connected to Hsp90 function. Principal component analysis of the entire dataset revealed that the effects of the mutants could be separated into three primary clusters. As evidence that Hsp90 mutants affect different pools of clients, simultaneous co-expression of two mutants in different clusters restored wild-type growth. Our data suggests that the ability of Hsp90 to sample a wide range of conformations allows the chaperone to mediate folding of a broad array of clients and that disruption of conformational flexibility results in client defects dependent on those states.
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来源期刊
Genetics
Genetics 生物-遗传学
CiteScore
6.20
自引率
6.10%
发文量
177
期刊介绍: GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.
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