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Ube2V2 Is a Rosetta Stone Bridging Redox and Ubiquitin Codes, Coordinating DNA Damage Responses
ACS Central Science ( IF 12.7 ) Pub Date : 2018-01-17 00:00:00 , DOI: 10.1021/acscentsci.7b00556
Yi Zhao , Marcus J. C. Long , Yiran Wang , Sheng Zhang , Yimon Aye 1
Affiliation  

Posttranslational modifications (PTMs) are the lingua franca of cellular communication. Most PTMs are enzyme-orchestrated. However, the reemergence of electrophilic drugs has ushered mining of unconventional/non-enzyme-catalyzed electrophile-signaling pathways. Despite the latest impetus toward harnessing kinetically and functionally privileged cysteines for electrophilic drug design, identifying these sensors remains challenging. Herein, we designed “G-REX”—a technique that allows controlled release of reactive electrophiles in vivo. Mitigating toxicity/off-target effects associated with uncontrolled bolus exposure, G-REX tagged first-responding innate cysteines that bind electrophiles under true kcat/Km conditions. G-REX identified two allosteric ubiquitin-conjugating proteins—Ube2V1/Ube2V2—sharing a novel privileged-sensor-cysteine. This non-enzyme-catalyzed-PTM triggered responses specific to each protein. Thus, G-REX is an unbiased method to identify novel functional cysteines. Contrasting conventional active-site/off-active-site cysteine-modifications that regulate target activity, modification of Ube2V2 allosterically hyperactivated its enzymatically active binding-partner Ube2N, promoting K63-linked client ubiquitination and stimulating H2AX-dependent DNA damage response. This work establishes Ube2V2 as a Rosetta-stone bridging redox and ubiquitin codes to guard genome integrity.

中文翻译:

Ube2V2是桥接氧化还原和泛素编码的Rosetta Stone,可协调DNA损伤反应

翻译后修饰(PTM)是手机通讯的通用语言。大多数PTM是经过酶促处理的。然而,亲电子药物的重新出现引发了非常规/非酶催化的亲电子信号通路的挖掘。尽管有最新动力推动利用具有动力学和功能优势的半胱氨酸进行亲电药物设计,但是识别这些传感器仍然具有挑战性。本文中,我们设计了“ G-REX”技术,该技术可在体内控制释放反应性亲电试剂。G-REX标记的第一反应先天半胱氨酸在真实的k cat / K m下结合亲电试剂,可减轻与不受控制的大剂量暴露相关的毒性/脱靶效应条件。G-REX鉴定了两种变构泛素结合蛋白-Ube2V1 / Ube2V2-共享了一种新型的特权传感器-半胱氨酸。这种非酶催化的PTM触发了对每种蛋白质特异的反应。因此,G-REX是鉴定新型功能性半胱氨酸的无偏方法。与调节靶标活性的常规活性位点/非活性位点半胱氨酸修饰相反,Ube2V2的修饰变构使其酶活性的结合伴侣Ube2N超活化,从而促进K63连接的客户泛素化并刺激H2AX依赖性DNA损伤反应。这项工作建立了Ube2V2作为Rosetta-stone桥接氧化还原和泛素代码以保护基因组完整性的功能。
更新日期:2018-01-17
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