美国威尔康奈尔医学Jared L. Johnson，Lewis C. Cantley，美国麻省理工学院Michael B. Yaffe和美国耶鲁大学医学院Benjamin E. Turk共同合作，近期取得重要工作进展。他们研究提出人酪氨酸激酶组的内在底物特异性观点。相关研究成果2024年5月8日在线发表于《自然》杂志上。
据介绍，后生动物体内酪氨酸（Tyr）残基上蛋白质的磷酸化作为协调组织生长的机制。多细胞真核生物通常具有50多种不同的蛋白质Tyr激酶，它们催化整个蛋白质组中数千个Tyr残基的磷酸化。给定的Tyr激酶如何在独特的Tyr位点磷酸化特定的蛋白质亚群，目前还只是部分了解。
研究人员使用组合肽阵列来分析所有人Tyr激酶的底物序列特异性。在全球范围内，Tyr激酶在磷酸化位点周围的最佳残基模式上表现出相当大的多样性，揭示了人类Tyr激酶组通过底物基序偏好的功能组织。利用这些信息，可以鉴定与磷酸化任何Tyr位点最相容的Tyr激酶。使用该激酶特异性简编对质谱磷酸蛋白质组学数据集的分析准确地鉴定了在用生长因子刺激、用抗癌药物治疗或致癌变体表达后在细胞中失调的特异性Tyr激酶。
此外，通过比较Tyr激酶和SH2磷酸酪氨酸（pTyr）结合结构域的序列特异性，自然得出已知Tyr信号网络的拓扑结构。
最后，研究人员发现，Tyr激酶的内在底物特异性从蠕虫到人类基本上保持不变，这表明Tyr激酶及其蛋白质底物序列之间的保真度在数亿年的进化过程中一直保持不变。
附：英文原文
Title: The intrinsic substrate specificity of the human tyrosine kinome
Author: Yaron-Barir, Tomer M., Joughin, Brian A., Huntsman, Emily M., Kerelsky, Alexander, Cizin, Daniel M., Cohen, Benjamin M., Regev, Amit, Song, Junho, Vasan, Neil, Lin, Ting-Yu, Orozco, Jose M., Schoenherr, Christina, Sagum, Cari, Bedford, Mark T., Wynn, R. Max, Tso, Shih-Chia, Chuang, David T., Li, Lei, Li, Shawn S.-C., Creixell, Pau, Krismer, Konstantin, Takegami, Mina, Lee, Harin, Zhang, Bin, Lu, Jingyi, Cossentino, Ian, Landry, Sean D., Uduman, Mohamed, Blenis, John, Elemento, Olivier, Frame, Margaret C., Hornbeck, Peter V., Cantley, Lewis C., Turk, Benjamin E., Yaffe, Michael B., Johnson, Jared L.
Issue&Volume: 2024-05-08
Abstract: Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1,2,3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4,5,6,7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.
DOI: 10.1038/s41586-024-07407-y
Source: https://www.nature.com/articles/s41586-024-07407-y
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
