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首页> 外文期刊>Biochemistry >The solution phase interaction between apolipoprotein(a) and plasminogen inhibits the binding of plasminogen to a plasmin-modified fibrinogen surface
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The solution phase interaction between apolipoprotein(a) and plasminogen inhibits the binding of plasminogen to a plasmin-modified fibrinogen surface

机译：载脂蛋白（a）和纤溶酶原之间的溶液相相互作用抑制了纤溶酶原与纤溶酶修饰的纤维蛋白原表面的结合

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In the present study, we assessed the binding of recombinant forms of apolipoprotein(a) [r-apo(a)] to plasminogen. Apo(a)-plasminogen interactions were demonstrated to be lysine-dependent, as they were abolished by the addition of epsilon-aminocaproic acid. Binding of r-apo(a) and plasma-derived Lp(a) to Glu-plasminogen was assessed in solution using a mutant form of recombinant plasminogen [Plg(S741C)] labeled at the active site with 5'-(iodoacetamido)fluorescein. High-affinity binding of apo(a) to plasminogen was observed with the 17-kringle r-apo(a) (Kd = 20.1 +/- 3.3 nM) as well as with plasma-derived Lp(a) (Kd = 5.58 +/- 0.08 nM). Binding studies using various truncated and mutant forms of r-apo(a) demonstrated that sequences within apo(a) kringle IV types 2-9 and the strong lysine binding site (LBS) in apo(a) kringle IV type 10 are not required for high-affinity binding to plasminogen. In all cases, the binding stoichiometry for the apo(a)-plasminogen interaction was determined to be 1:1. Binding data obtained using a 17-kringle r-apo(a) derivative lacking the protease-like domain (17KDeltaP; Kd = 3158 +/- 138 nM) indicate that sequences within the protease-like domain of apo(a) mediate its interaction with LBS in plasminogen. We determined that r-apo(a) and plasminogen bind to distinct sites on plasmin-modified fibrinogen with the concentration of plasminogen binding sites exceeding the concentration of r-apo(a) sites by a factor of 10. Furthermore, r-apo(a) is capable of inhibiting the binding of plasminogen to plasmin-modified fibrinogen surfaces, an effect which we show is attributable to the formation of a solution phase apo(a)/plasminogen complex which exhibits a greatly reduced affinity for plasminogen binding sites on plasmin-modified fibrinogen. The results of this study provide new insights into the mechanism by which apo(a) and Lp(a) may inhibit fibrinolysis, thus contributing to the atherothrombotic risk associated with this lipoprotein.
机译：在本研究中，我们评估了重组形式的载脂蛋白（a）[r-apo（a）]与纤溶酶原的结合。 Apo（a）-纤溶酶原相互作用被证明是赖氨酸依赖性的，因为添加ε-氨基己酸消除了它们的相互作用。在溶液中使用在活性部位标记有5'-（碘乙酰胺基）荧光素的重组型纤溶酶原[Plg（S741C）]的突变形式，评估了r-apo（a）和血浆来源的Lp（a）与Glu-纤溶酶原的结合。在17环r-apo（a）（Kd = 20.1 +/- 3.3 nM）以及血浆来源的Lp（a）（Kd = 5.58 +）中观察到apo（a）与纤溶酶原的高亲和力结合/-0.08 nM）。使用各种截短和突变形式的r-apo（a）进行的结合研究表明，不需要apo（a）kringle IV 2-9型中的序列和apo（a）kringle IV 10型中的强赖氨酸结合位点（LBS）与纤溶酶原的高亲和力结合。在所有情况下，载脂蛋白（a）-纤溶酶原相互作用的结合化学计量均被确定为1：1。使用缺乏蛋白酶样结构域（17KDeltaP; Kd = 3158 +/- 138 nM）的17-kringle r-apo（a）衍生物获得的结合数据表明apo（a）的蛋白酶样结构域内的序列介导了其相互作用与纤溶酶原中的LBS结合使用。我们确定r-apo（a）和纤溶酶原与纤溶酶修饰的纤维蛋白原上的不同位点结合，其纤溶酶原结合位点的浓度比r-apo（a）位点的浓度高10倍。此外，r-apo（ a）能够抑制纤溶酶原与纤溶酶修饰的纤维蛋白原表面的结合，我们显示出这种作用归因于溶液相载脂蛋白（a）/纤溶酶原复合物的形成，该溶液相对纤溶酶上的纤溶酶原结合位点的亲和力大大降低修饰的纤维蛋白原。这项研究的结果为apo（a）和Lp（a）抑制纤维蛋白溶解的机制提供了新见解，从而增加了与此脂蛋白相关的动脉粥样硬化血栓形成的风险。

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