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人类单链尿素酶类型等离子体激活剂 (uPA) 的自动激活
Constanza Torres-Paris1, Yueyi Chen1, Lufan Xiao1
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA.
The Journal of biological chemistry
|August 22, 2023
概括
泌尿酸酶类型的塑原激活剂 (uPA) 酶原通过构造变化和裂变自动激活,即使在突变的部位. 这一发现澄清了uPA正反循环的启动,这对于蛋白酶激活至关重要.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 蛋白酶研究的研究
背景情况:
- 血清蛋白酶,如尿酶类型的塑原激活剂 (uPA),以非活跃的酶原合成,需要蛋白质分解裂变才能激活.
- uPA的激活涉及与等离子体的积极反循环,但启动机制仍然不清楚.
研究的目的:
- 调查非活性单链uPA (scuPA) 和活性双链uPA (tcuPA) 之间的动态差异.
- 阐明scuPA的自动激活机制,并解决有关其启动的争议.
主要方法:
- 使用二交换质谱法 (HDX-MS) 来分析形状动态.
- 用局部导向的突变发生法来研究裂部位的特异性.
主要成果:
- 与不活跃的scuPA相比,HDX-MS显示活跃tcuPA的C端β桶和N端区域的动态减少.
- 不活跃的scuPA可以在储存时自发激活,独立于外部蛋白酶.
- tcuPA通过在K158分裂自动激活scuPA,也可以在突变的K158位点分裂.
- tcuPA还在K135或K136处分裂scuPA,释放可溶性蛋白酶域.
- 等离子素在K158时完全分裂scuPA,比tcuPA的速度更快.
结论:
- 该研究提出了一种uPA自动激活的机制,涉及多个部位的构造变化和裂变,包括突变的部位.
- 细胞表面上的uPA受体的二元化可能会促进scuPA自主激活.
- 这些发现解决了关于启动uPA激活级联的长期问题.
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