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Direct cysteine sulfenylation drives activation of the Src kinase.
Nature Communications ( IF 14.7 ) Pub Date : 2018-10-30 , DOI: 10.1038/s41467-018-06790-1
David E Heppner 1, 2, 3 , Christopher M Dustin 1 , Chenyi Liao 4 , Milena Hristova 1 , Carmen Veith 1 , Andrew C Little 1 , Bethany A Ahlers 5 , Sheryl L White 6 , Bin Deng 5 , Ying-Wai Lam 5 , Jianing Li 4 , Albert van der Vliet 1
Affiliation  

The Src kinase controls aspects of cell biology and its activity is regulated by intramolecular structural changes induced by protein interactions and tyrosine phosphorylation. Recent studies indicate that Src is additionally regulated by redox-dependent mechanisms, involving oxidative modification(s) of cysteines within the Src protein, although the nature and molecular-level impact of Src cysteine oxidation are unknown. Using a combination of biochemical and cell-based studies, we establish the critical importance of two Src cysteine residues, Cys-185 and Cys-277, as targets for H2O2-mediated sulfenylation (Cys-SOH) in redox-dependent kinase activation in response to NADPH oxidase-dependent signaling. Molecular dynamics and metadynamics simulations reveal the structural impact of sulfenylation of these cysteines, indicating that Cys-277-SOH enables solvent exposure of Tyr-416 to promote its (auto)phosphorylation, and that Cys-185-SOH destabilizes pTyr-527 binding to the SH2 domain. These redox-dependent Src activation mechanisms offer opportunities for development of Src-selective inhibitors in treatment of diseases where Src is aberrantly activated.

中文翻译:


直接半胱氨酸磺酰化驱动 Src 激酶的激活。



Src 激酶控制细胞生物学的各个方面,其活性受到蛋白质相互作用和酪氨酸磷酸化诱导的分子内结构变化的调节。最近的研究表明,Src 还受到氧化还原依赖性机制的调节,涉及 Src 蛋白内半胱氨酸的氧化修饰,尽管 Src 半胱氨酸氧化的性质和分子水平影响尚不清楚。通过结合生化和细胞研究,我们确定了两个 Src 半胱氨酸残基 Cys-185 和 Cys-277 作为氧化还原依赖性激酶激活反应中 H2O2 介导的磺酰化 (Cys-SOH) 靶标的至关重要性NADPH 氧化酶依赖性信号传导。分子动力学和元动力学模拟揭示了这些半胱氨酸磺酰化的结构影响,表明 Cys-277-SOH 使 Tyr-416 能够暴露在溶剂中,促进其(自)磷酸化,而 Cys-185-SOH 使 pTyr-527 与 pTyr-527 结合不稳定。 SH2 域。这些氧化还原依赖性 Src 激活机制为开发 Src 选择性抑制剂以治疗 Src 异常激活的疾病提供了机会。
更新日期:2018-10-31
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