Agarwal Vaibhav, Talens Simone, Grandits Alexander M, Blom Anna M
From the Medical Protein Chemistry, Translational Medicine, Lund University, 20502 Malmö, Sweden.
From the Medical Protein Chemistry, Translational Medicine, Lund University, 20502 Malmö, Sweden
J Biol Chem. 2015 Jul 24;290(30):18333-42. doi: 10.1074/jbc.M114.619494. Epub 2015 Jun 11.
The complement, coagulation, and fibrinolytic systems are crucial for the maintenance of tissue homeostasis. To date numerous interactions and cross-talks have been identified between these cascades. In line with this, here we propose a novel, hitherto unknown interaction between the complement inhibitor C4b-binding protein (C4BP) and plasminogen of the fibrinolytic pathway. Binding of C4BP to Streptococcus pneumoniae is a known virulence mechanism of this pathogen and it was increased in the presence of plasminogen. Interestingly, the acute phase variant of C4BP lacking the β-chain and protein S binds plasminogen much stronger than the main isoform containing the β-chain and protein S. Indeed, the complement control protein (CCP) 8 domain of C4BP, which would otherwise be sterically hindered by the β-chain, primarily mediates this interaction. Moreover, the lysine-binding sites in plasminogen kringle domains facilitate the C4BP-plasminogen interaction. Furthermore, C4BP readily forms complexes with plasminogen in fluid phase and such complexes are present in human serum and plasma. Importantly, whereas the presence of plasminogen did not affect the factor I cofactor activity of C4BP, the activation of plasminogen by urokinase-type plasminogen activator to active plasmin was significantly augmented in the presence of C4BP. Taken together, our data demonstrate a novel interaction between two proteins of the complement and fibrinolytic system. Most complexes might be formed during the acute phase of inflammation and have an effect on the homeostasis at the site of injury or acute inflammation.
补体、凝血和纤维蛋白溶解系统对于维持组织稳态至关重要。迄今为止，已确定这些级联反应之间存在众多相互作用和串扰。与此一致的是，我们在此提出补体抑制剂C4b结合蛋白（C4BP）与纤维蛋白溶解途径中的纤溶酶原之间存在一种新的、迄今未知的相互作用。C4BP与肺炎链球菌的结合是该病原体已知的毒力机制，并且在纤溶酶原存在的情况下这种结合会增强。有趣的是，缺乏β链和蛋白S的C4BP急性期变体比含有β链和蛋白S的主要异构体与纤溶酶原的结合要强得多。实际上，C4BP的补体控制蛋白（CCP）8结构域主要介导这种相互作用，否则它会受到β链的空间位阻。此外，纤溶酶原kringle结构域中的赖氨酸结合位点促进了C4BP与纤溶酶原的相互作用。此外，C4BP很容易在液相中与纤溶酶原形成复合物，并且这种复合物存在于人的血清和血浆中。重要的是，虽然纤溶酶原的存在不影响C4BP的I因子辅因子活性，但在C4BP存在的情况下，尿激酶型纤溶酶原激活剂将纤溶酶原激活为活性纤溶酶的过程显著增强。综上所述，我们的数据证明了补体和纤维蛋白溶解系统的两种蛋白质之间存在一种新的相互作用。大多数复合物可能在炎症急性期形成，并对损伤部位或急性炎症处的稳态产生影响。
