Farrell D H, Thiagarajan P
Department of Biochemistry, University of Washington, Seattle 98195.
J Biol Chem. 1994 Jan 7;269(1):226-31.
Platelet aggregation is mediated by the interaction of fibrinogen with platelet membrane glycoprotein IIb-IIIa, a member of the integrin family (integrin alpha IIb beta 3). Three different binding sites on fibrinogen for IIb-IIIa have been proposed, two RGD-containing sequences in the alpha chain and one dodecapeptide sequence at the carboxyl terminus of the gamma chain. However, recent evidence shows that mutations in either of the alpha chain sequences have no effect on platelet aggregation, whereas the substitution of a variant gamma chain (gamma') for the gamma chain results in a major reduction in platelet aggregation activity. The present investigation demonstrates that the gamma' chain shows decreased binding to IIb-IIIa as measured by direct binding experiments. In addition, adhesion studies indicate that the binding of both stimulated and unstimulated platelets to immobilized fibrinogens is mediated primarily through the gamma chain carboxyl terminus. Furthermore, a peptide corresponding to the carboxyl terminus of the gamma chain inhibits fibrinogen binding and platelet adhesion, whereas a peptide corresponding to the carboxyl terminus of the gamma' chain is significantly less inhibitory. These data show that the defective platelet aggregation activity of the fibrinogen gamma' chain is due to decreased binding to platelet glycoprotein IIb-IIIa.
血小板聚集是由纤维蛋白原与血小板膜糖蛋白IIb-IIIa（整合素家族成员，整合素αIIbβ3）相互作用介导的。已提出纤维蛋白原上IIb-IIIa的三个不同结合位点，一个在α链上的两个含RGD序列，另一个在γ链羧基末端的十二肽序列。然而，最近的证据表明，α链序列中任一个的突变对血小板聚集没有影响，而用变体γ链（γ'）替代γ链会导致血小板聚集活性大幅降低。本研究表明，通过直接结合实验测量，γ'链与IIb-IIIa的结合减少。此外，黏附研究表明，受刺激和未受刺激的血小板与固定化纤维蛋白原的结合主要通过γ链羧基末端介导。此外，对应于γ链羧基末端的肽抑制纤维蛋白原结合和血小板黏附，而对应于γ'链羧基末端的肽的抑制作用明显较小。这些数据表明，纤维蛋白原γ'链的血小板聚集活性缺陷是由于与血小板糖蛋白IIb-IIIa的结合减少所致。
