The fitness cost of spurious phosphorylation.

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Journal Pub Date : 2024-10-01 Epub Date: 2024-09-10 DOI:10.1038/s44318-024-00200-7
David Bradley, Alexander Hogrebe, Rohan Dandage, Alexandre K Dubé, Mario Leutert, Ugo Dionne, Alexis Chang, Judit Villén, Christian R Landry
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Abstract

The fidelity of signal transduction requires the binding of regulatory molecules to their cognate targets. However, the crowded cell interior risks off-target interactions between proteins that are functionally unrelated. How such off-target interactions impact fitness is not generally known. Here, we use Saccharomyces cerevisiae to inducibly express tyrosine kinases. Because yeast lacks bona fide tyrosine kinases, the resulting tyrosine phosphorylation is biologically spurious. We engineered 44 yeast strains each expressing a tyrosine kinase, and quantitatively analysed their phosphoproteomes. This analysis resulted in ~30,000 phosphosites mapping to ~3500 proteins. The number of spurious pY sites generated correlates strongly with decreased growth, and we predict over 1000 pY events to be deleterious. However, we also find that many of the spurious pY sites have a negligible effect on fitness, possibly because of their low stoichiometry. This result is consistent with our evolutionary analyses demonstrating a lack of phosphotyrosine counter-selection in species with tyrosine kinases. Our results suggest that, alongside the risk for toxicity, the cell can tolerate a large degree of non-functional crosstalk as interaction networks evolve.

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虚假磷酸化的健康代价
信号转导的保真度要求调控分子与其同源靶标结合。然而,拥挤的细胞内部存在着功能上不相关的蛋白质之间发生脱靶相互作用的风险。这种脱靶相互作用如何影响适存性尚不清楚。在这里,我们利用酿酒酵母诱导表达酪氨酸激酶。由于酵母缺乏真正的酪氨酸激酶,因此产生的酪氨酸磷酸化在生物学上是假的。我们设计了 44 株酵母菌株,每株表达一种酪氨酸激酶,并对其磷酸化蛋白组进行了定量分析。分析结果显示,约有 30,000 个磷酸化位点映射到约 3500 个蛋白质上。产生的虚假 pY 位点数量与生长下降密切相关,我们预测超过 1000 个 pY 事件是有害的。不过,我们也发现,许多虚假 pY 位点对适应性的影响可以忽略不计,这可能是因为它们的化学计量较低。这一结果与我们的进化分析表明在具有酪氨酸激酶的物种中缺乏磷酸化酪氨酸反选择的结果是一致的。我们的研究结果表明,随着相互作用网络的进化,除了毒性风险之外,细胞还能容忍很大程度的无功能串扰。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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