Coevolutionary patterns in plasminogen activation
Coevolutionary patterns in plasminogen activation
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DOI：
10.1073/pnas.1631716100
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发表时间：
2003-08-05
影响因子：
11.1
通讯作者：
Reed, GL
中科院分区：
文献类型：
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作者：
Gladysheva, IP;Turner, RB;Reed, GL
由纤溶酶原（Pg）激活剂（PA）产生纤溶酶是动物中的生理过程，其溶解血凝块并促进伤口愈合、血管生长以及正常细胞和癌细胞的迁移。致病细菌已经进化出PA [例如，链激酶（SK）和葡激酶]，它们利用Pg系统感染动物。动物PA具有裂解广谱动物Pgs的保守能力，但细菌PA裂解不同动物Pgs的能力令人惊讶地受到限制。我们发现，一个原型细菌PA（SK）与动物PGS的活性谱可以深刻地改变突变，影响分子间的互补性，参与复杂的形成或底物结合的网站。动物纤溶酶与接近的结构同源物（胰蛋白酶和胰凝乳蛋白酶），不是入侵细菌的分子靶标的比较序列分析表明，纤溶酶中与SK相互作用的位点优先靶向突变。相反，在SK中激活人Pg的分子间接触位点比分子中的其它基因座或比在其它SK中激活非人Pg的相同位点更高度保守。我们建议，在接触位点的分子间互补性的主动调制。SK和Pg之间的竞争可能代表了生存战中的竞争性进化策略，动物试图逃避细菌入侵，而细菌奋进入侵它们的动物宿主。
The generation of plasmin by plasminogen (Pg) activators (PAs) is a physiologic process in animals that dissolves blood clots and promotes wound healing, blood vessel growth, and the migration of normal and cancerous cells. Pathogenic bacteria have evolved PAs [e.g., streptokinase (SK) and staphylokinase] that exploit the Pg system to infect animals. Animal PAs have a conserved ability to cleave a wide spectrum of animal Pgs, but the ability of bacterial PAs to cleave different animal Pgs is surprisingly restricted. We show that the spectrum of activity of an archetypal bacterial PA (SK) with animal Pgs can be profoundly altered by mutations that affect intermolecular complementarity at sites that participate in complex formation or substrate binding. Comparative sequence analysis of animal plasmins vs. close structural homologues (trypsin and chymotrypsin) that are not molecular targets for invading bacteria indicates that the sites in plasmin that interact with SK are preferentially targeted for mutation. Conversely, intermolecular contact sites in SKs that activate human Pg are more highly conserved than other loci in the molecule or than the same sites in other SKs that activate non-human Pgs. We propose that active modulation of intermolecular complementarity at sites of contact. between SK and Pg may represent a competitive evolutionary strategy in a survival battle, whereby animals seek to evade bacterial invasion, and bacteria endeavor to invade their animal hosts.