热力学和选择等离子体激活剂抑制剂-1 延迟过渡的选择
bioRxiv : the preprint server for biology
|June 12, 2025
概括
深度突变扫描揭示了蛋白质的稳定性,而不仅仅是功能,是理解Plasminogen激活剂抑制剂-1 (PAI-1) 延迟的关键. 进化分析显示了PAI-1的存在.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 进化生物学 进化生物学
背景情况:
- 血原激活剂抑制剂-1 (PAI-1) 是一种具有转移稳定的活性构成的血清蛋白酶抑制剂 (SERPIN).
- 与其他SERPIN不同的是,PAI-1迅速过渡到潜伏状态.
- 了解PAI-1的结构动态对于其功能和调节至关重要.
研究的目的:
- 通过使用深度突变扫描 (DMS) 调查单氨基酸替代对PAI-1的延迟过渡和尿素酶类型等离子素激活剂 (uPA) 抑制的影响.
- 评估变异效应预测因子和蛋白质稳定性预测因子对PAI-1的功能和结构变化的预测能力.
- 探索PAI-1的抑制功能和热力学稳定性的进化约束.
主要方法:
- 深度突变扫描 (DMS) 来评估PAI-1中约92%单氨基酸替代物的影响.
- 使用的变异效应预测器 (EVE,AlphaMissense,CPT) 和蛋白质稳定性预测器 (EvoEF,FoldX).
- 在脊椎动物物种中分析了PAI-1序列的进化保存.
主要成果:
- 变异效应预测器在uPA抑制方面准确区分了功能性与非功能性PAI-1,但在延迟过渡方面失败了.
- 蛋白质稳定性预测指标表明,能量屏障的变化驱动了PAI-1延迟过渡.
- 无论是PAI-1的uPA抑制,还是其活性构造的热力学不稳定性,都在进行净化选择,限制序列变化.
结论:
- 蛋白质稳定性和热力学原理对于解释PAI-1延迟的DMS数据至关重要,补充了传统的变异效应预测器.
- 进化分析强调了PAI-1上保留的功能和稳定性约束.
- 在SERPIN中DMS的附带效应可能需要综合方法,考虑到蛋白质热力学和进化背景.
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