Enhancement of rabbit protein S anticoagulant cofactor activity in vivo by modulation of the protein S C4B binding protein interaction.
Enhancement of rabbit protein S anticoagulant cofactor activity in vivo by modulation of the protein S C4B binding protein interaction.
复制标题
通过调节蛋白 S C4B 结合蛋白相互作用增强兔蛋白 S 体内抗凝辅因子活性。
DOI：
10.1172/jci114926
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发表时间：
1990
期刊：
影响因子：
--
通讯作者：
Walker,FJ
中科院分区：
文献类型：
--
作者：
Weinstein,RE;Walker,FJ
最近已经观察到蛋白S的羧基末端区域参与蛋白S和C4 b结合蛋白之间的相互作用（步行者，F. J.，1989年。J.Biol.Chem.264：17645-17658）。一个合成的肽，GVQLDLDEAI，对应于该区域的蛋白S已被用来研究蛋白S/C4 b结合蛋白在体外和体内的相互作用。兔活化蛋白C具有种特异性抗凝活性，兔蛋白S作为辅因子发挥作用。在血浆中，发现兔蛋白S与C4 b结合蛋白复合。GVQLDLDEAI可抑制这种相互作用，从而增强兔活化蛋白C的抗凝活性。肽的作用可以通过同时加入人或兔C4 b结合蛋白来阻断。当输注到兔子，GVQLDLDEAI从循环中清除，半衰期为80分钟。这是显着低于类似大小的对照肽（半衰期为15分钟）的清除速度，但远远超过牛蛋白S，一个更大的蛋白质（半衰期为15小时）。发现输注GVQLDLDEAI后从兔中取出的血浆样品具有增加的游离蛋白S浓度，并显示出以剂量依赖性方式通过兔活化蛋白C离体增强的抗凝作用。半数最大效应的浓度（5 μ M）与体外观察到的浓度非常相似。这些结果表明，蛋白S和C4 b结合蛋白之间复合物的形成在体内蛋白S活性的调节中是重要的，并且这种相互作用的调节允许人们影响蛋白C途径的抗凝活性。图片
The carboxy-terminal region of protein S has been recently been observed to be involved in the interaction between protein S and C4b-binding protein (Walker, F. J. 1989. J. Biol. Chem. 264:17645-17658). A synthetic peptide, GVQLDLDEAI, corresponding to that region of protein S has been used to investigate the protein S/C4b-binding protein interaction in vitro and in vivo. Rabbit activated protein C possesses species-specific anticoagulant activity for which rabbit protein S functions as a cofactor. In plasma, rabbit protein S is found in complex with C4b-binding protein. GVQLDLDEAI can inhibit this interaction, resulting in enhancement of the anticoagulant activity of rabbit activated protein C. The effect of the peptide can be blocked by the concurrent addition of human or rabbit C4b-binding protein. When infused into rabbits, GVQLDLDEAI was cleared from the circulation with a half-life of 80 min. This is significantly less rapid than the clearance of similarly sized control peptides (half-life of 15 min), but much more than that of bovine protein S, a much larger protein (half-life of 15 h). Plasma samples removed from the rabbits after infusion with GVQLDLDEAI were found to have increased concentrations of free protein S and to show enhanced anticoagulation by rabbit activated protein C ex vivo in a dose-dependent manner. The concentration for half-maximal effect (5 microM) was very similar to that observed in vitro. These results suggest that the formation of a complex between protein S and C4b-binding protein is important in the regulation of protein S activity in vivo, and that modulation of this interaction allows one to influence the anticoagulant activity of the protein C pathway.Images