Protein S-sulfenylation is a fleeting molecular switch that regulates non-enzymatic oxidative folding.
Protein S-sulfenylation is a fleeting molecular switch that regulates non-enzymatic oxidative folding.
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DOI：
10.1038/ncomms12490
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发表时间：
2016-08-22
影响因子：
16.6
通讯作者：
Garcia-Manyes S
中科院分区：
文献类型：
--
作者：
Beedle AE;Lynham S;Garcia-Manyes S
翻译后修饰 S-磺酰化是氧化应激的关键传感器。然而，由于其转瞬即逝的性质，蛋白质中次磺酸的动力学在很大程度上仍然难以捉摸。在这里，我们使用单分子力钳光谱和质谱法直接捕获嵌入肌联蛋白单个 Ig 结构域核心内的单个次磺酸的反应性。我们的结果表明，次磺酸是一种重要的短寿命中间体，它以构象依赖性方式决定蛋白质的命运。当暴露于溶液中时，次磺酸迅速发生进一步的化学修饰，导致不可逆的蛋白质错误折叠；当隐藏在蛋白质的微环境中时，它很容易与邻近的硫醇缩合，形成保护性二硫键，从而有助于蛋白质的功能折叠。这种非酶促氧化折叠机制为生理上暴露于机械力的蛋白质（例如心脏肌联蛋白）的氧化还原调节硬度提供了合理的解释。 蛋白质 S-磺酰化是一种翻译后修饰，可充当氧化还原氧化应激的传感器。作者在此表明，机械解折叠后，次磺酸驱动二硫键重组并引导非酶促氧化折叠。
The post-translational modification S-sulfenylation functions as a key sensor of oxidative stress. Yet the dynamics of sulfenic acid in proteins remains largely elusive due to its fleeting nature. Here we use single-molecule force-clamp spectroscopy and mass spectrometry to directly capture the reactivity of an individual sulfenic acid embedded within the core of a single Ig domain of the titin protein. Our results demonstrate that sulfenic acid is a crucial short-lived intermediate that dictates the protein's fate in a conformation-dependent manner. When exposed to the solution, sulfenic acid rapidly undergoes further chemical modification, leading to irreversible protein misfolding; when cryptic in the protein's microenvironment, it readily condenses with a neighbouring thiol to create a protective disulfide bond, which assists the functional folding of the protein. This mechanism for non-enzymatic oxidative folding provides a plausible explanation for redox-modulated stiffness of proteins that are physiologically exposed to mechanical forces, such as cardiac titin. Protein S-sulfenylation is a posttranslational modification that can act as a sensor of redox oxidative stress. Here the authors show that, following mechanical unfolding, sulfenic acid drives disulfide bond reformation and guides non-enzymatic oxidative folding.