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与DHPS的ERK1/2相互作用调节eIF5A脱氧基化,独立于ERK激酶活性

Andrew E Becker¹, Paweł Kochanowski², Pui-Kei Wu¹

¹Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

|October 11, 2024

概括

细胞外调节酶1/2 (ERK1/2) 通过调节脱氧化酶合成酶 (DHPS) 和真核转化启动因子5A (eIF5A) 相互作用,独立于催化活性,通过非细胞调节调节脱氧化酶.

科学领域:

分子生物学分子生物学
细胞信号传递细胞信号传递
生物化学生物化学

背景情况:

细胞外调节激酶1/2 (ERK1/2) 是细胞过程的关键调节者.
脱氧基氨酸合成酶 (DHPS) 催化了转化后转化对真核细胞转化启动因子5A (eIF5A) 的转化后修饰,这对转化至关重要.
对于ERK1/2和DHPS在调节脱氧化的相互作用还没有完全理解.

研究的目的:

研究ERK1/2在调节DHPS和eIF5A之间的相互作用中的非激酶功能.
阐明DHPS-ERK2复合体形成的结构基础及其对酶活性的影响.
区分ERK1/2在脱氧基化中的依赖激酶和独立激酶的作用.

主要方法:

低温电子显微镜 (cryo-EM) 用于确定DHPS-ERK2复合物的结构.
在各种信号条件下进行细胞测试以评估DHPS-ERK1/2和DHPS-eIF5A相互作用.
位点定向的突变发生,以探究特定ERK2基因和域的作用.

主要成果:

拉夫/MEK/ERK激活减少了DHPS-ERK1/2的相互作用,但增加了DHPS-eIF5A的关联.
冷-EM结构揭示了ERK2在物理上阻断了基质进入DHPS活性部位,在体外抑制了脱氧化化.
在ERK2激活循环的修改,而不是催化部位,延长了DHPS-ERK2相互作用,独立于Raf/MEK信号.
ERK2 Ser-Pro-Ser 图案,而不是正规的对接点,调节了DHPS-ERK2复合体.

结论:

ERK1/2通过基因酶依赖和基因酶独立的机制动态调节DHPS-eIF5A相互作用.
由于ERK1/2的非激酶功能,它通过对基质与DHPS结合的硬质性阻碍来抑制脱氧基化.
ERK1/2激酶活性对于调节DHPS和eIF5A的表达水平至关重要.

关键词:

科普:分子生物学分子生物学这就是MAP激酶.在Raf/MEK/ERK路径中.低温电磁波冷却器 (Cryo-EM) 是一个非常好的方法.低温电子显微镜的低温电子显微镜脱氧基氨酸合成酶是什么单核细胞转化启动因子5A 细胞外信号调节激酶1/2 细胞外信号调节激酶 1/2 催化剂的含量是低的阴茎下垂体 (hypusine) 是一个类型.非酶效应的非酶效应

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