高分子量基因因与同类物prekallikrein和XI因子的相互作用:对表面诱导凝血的重要性
Bassem M Mohammed1, Mao-Fu Sun2, Qiufang Cheng2
1Edward A. Doisy Research Center, Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri, USA.
Journal of thrombosis and haemostasis : JTH
|October 9, 2023
概括
高分子量基因因子 (HK) 结合D6域中的prekallikrein (PK) 和XI因子 (FXI),对于血栓形成中的FXI激活至关重要. 这种相互作用对凝血至关重要,尽管HK对血液静止不必.
科学领域:
- 生物化学 生物化学
- 血液学 血液学 血液学
- 分子生物学分子生物学
背景情况:
- 高分子量基因素 (HK) 在血中循环,可以自由或结合到前基因素 (PK) 或XI因子 (FXI).
- 在接触激活过程中,据信HK将PK和FXI固定在表面上,促进它们转化为活性蛋白酶.
- 缺乏HK的小鼠表现出正常的血液静止,但表现出对受伤诱导的动脉血栓形成的抵抗力.
研究的目的:
- 精确确定HK-D6域内负责PK和FXI结合的特定氨基酸.
- 阐明HK-PK和HK-FXI相互作用在凝血级联中的重要性.
主要方法:
- 为PK/FXI结合和凝固试验生成和分析了24种HK变异,其中D6域中具有氨酸替代物 (残留物542-613).
- 研究了带有和没有HK的等离子体表面诱导的FXI和PK激活.
- 使用Kng1-/-小鼠 (缺乏HK) 补充人类或小鼠HK以评估动脉血栓形成.
主要成果:
- 在HK-D6域内确定了PK和FXI的重叠绑定站点.
- 具有FXI结合受损的HK变体与具有PK结合受损的HK变体相比,在HK缺乏的血中显示出激活的部分血栓形成时间的调整较差.
- 缺乏HK对FXI激活的负面影响比对血PK激活的负面影响更为明显.
- 人类HK在纠正HK缺陷小鼠的动脉血栓形成方面表现出有限的有效性,这是由于与小鼠FXI的错误结合.
结论:
- 在体外和体内,HK-FXI相互作用对于接触激活诱导的凝血至关重要,突出了它在血栓形成中的作用.
- 尽管临床观察表明因子XI (FXI) 对于静血而不是HK是必要的,但HK-FXI相互作用对某些凝血过程至关重要.
- 进一步的研究可能会探索这种相互作用在其他FXI中介活动中的作用.
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