在Fyn SH2域中的突变诱导的刚性增强了pY结合亲和力,但代价是特异性
Li Deng1, Yang Zou1, Junbao Zhu2
1School of Health and Life Sciences, University of Health and Rehabilitation Sciences, 369 Dengyun Road, Qingdao 266071, China. lilei@uhrs.edu.cn.
Physical chemistry chemical physics : PCCP
|June 9, 2025
概括
在Fyn SH2域中发生的突变增加了结合口袋的刚性,增强了氨酸化 (pY) 相互作用,但降低了特异性. 这会影响细胞信号的动态.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- SH2域对于通过结合氨酸酸化 (pY) 来进行细胞信号传递至关重要.
- 之前的研究阐明了具有高pY-亲和度的Fyn SH2突变的结构方面.
- 这些突变对SH2域-相互作用的动态影响以前未被探索.
研究的目的:
- 研究Fyn SH2域突变对pY-相互作用的动态后果.
- 为如何突变改变Fyn SH2域和pY-结合提供动态见解.
- 了解动态稳定性在SH2域-识别中的作用.
主要方法:
- 野生类型和突变Fyn SH2域的广泛的全原子分子动力学模拟.
- 模拟包括与特定的pY- (EPQpYEEIPIYL) 相关的孤立域及其复合体.
- 对模拟数据进行比较分析,以评估动态变化.
主要成果:
- 突变显著改变了非结构区域的动态稳定性和域-接口.
- 在pY结合口袋和整体SH2域结构 (中央β片,终端区域) 中,突变体的刚性和稳定性增加.
- 增加的刚性增强了pY结合,但在+3位置削弱了相互作用,降低了特异性.
结论:
- SH2域-pY-相互作用取决于pY结合口袋结构和总体域动态稳定性.
- 突变影响SH2域动态,影响结合亲和力和特异性.
- 这些发现可以指导SH2域的工程,以识别各种翻译后修改.
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