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通过酸化折叠一个内在无序的蛋白质作为一个调节开关

Alaji Bah¹, Robert M Vernon¹, Zeba Siddiqui²

¹1] Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada [2] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

|December 24, 2014

概括

多位酸化会导致本质上失序的蛋白4E-BP2折叠,阻止其与eIF4E的相互作用. 这种酸化诱导的折叠揭示了调节蛋白质功能和生物过程的新机制.

科学领域:

分子生物学分子生物学
蛋白质生物化学蛋白质生物化学
细胞信号传递细胞信号传递

背景情况:

内在无序的蛋白质 (IDP) 调节重要的细胞过程,如转录和翻译.
虽然许多IDP在绑定时过渡到有序结构,但也已知有规范的顺序到失序的过渡.
翻译后的修改可以诱导内部开发人员的结构变化,但这种机制尚未得到充分证实.

研究的目的:

调查翻译后修改是否可以诱导内在无序蛋白质的折叠.
阐明多位酸化如何影响4E-BP2:eIF4E相互作用的机制.
探索一种由内在无序的蛋白质调节的新型生物调节模式.

主要方法:

研究了内在失调的蛋白质4E-BP2,它是翻译启动的关键调节者.
使用生物化学测试来分析4E-BP2和eIF4E之间的相互作用.
在T37和T46使用生物物理技术对4E-BP2在酸化后的结构变化进行了研究.

主要成果:

在T37和T46的多位酸化会诱导4E-BP2中的稳定折叠,形成β域.
这种酸化诱导的折叠封存了eIF4E结合动机,显著降低了结合亲和力.
在eIF4E结合时,pT37pT46 4E-BP2的折叠状态经历了从秩序到混乱的过渡,亲和力降低了100倍.

结论:

酸化诱导的折叠是调节4E-BP2:eIF4E相互作用的关键机制.
这项研究表明了一种新的调节策略,涉及到酸化诱导的蛋白质折叠的稳定.
突出了通过内在无序蛋白质调节的生物调节的新范式.

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