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首页> 外文期刊>Journal of Molecular Biology >Plasminogen activator inhibitor-2 is highly tolerant to P8 residue substitution--implications for serpin mechanistic model and prediction of nsSNP activities.
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Plasminogen activator inhibitor-2 is highly tolerant to P8 residue substitution--implications for serpin mechanistic model and prediction of nsSNP activities.

机译：纤溶酶原激活物抑制剂2高度耐受P8残基取代-对丝氨酸蛋白酶抑制剂机制模型和nsSNP活性的预测具有重要意义。

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The serine protease inhibitor (serpin) superfamily is involved in a wide range of cellular processes including fibrinolysis, angiogenesis, apoptosis, inflammation, metastasis and viral pathogenesis. Here, we investigate the unique mousetrap inhibition mechanism of serpins through saturation mutagenesis of the P8 residue for a typical family member, plasminogen activator inhibitor-2 (PAI-2). A number of studies have proposed an important role for the P8 residue in the efficient insertion and stabilisation of the cleaved reactive centre loop (RCL), which is a key event in the serpin inhibitory mechanism. The importance of this residue for inhibition of the PAI-2 protease target urinary plasminogen activator (urokinase, uPA) is confirmed, although a high degree of tolerance to P8 substitution is observed. Out of 19 possible PAI-2 P8 mutants, 16 display inhibitory activities within an order of magnitude of the wild-type P8 Thr species. Crystal structures of complexes between PAI-2 and RCL-mimicking peptides with P8 Met or Asp mutations are determined, and structural comparison with the wild-type complex substantiates the ability of the S8 pocket to accommodate disparate side-chains. These data indicate that the identity of the P8 residue is not a determinant of efficient RCL insertion, and provide further evidence for functional plasticity of key residues within enzyme structures. Poor correlation of observed PAI-2 P8 mutant activities with a range of physicochemical, evolutionary and thermodynamic predictive indices highlights the practical limitations of existing approaches to predicting the molecular phenotype of protein variants.
机译：丝氨酸蛋白酶抑制剂（serpin）超家族涉及广泛的细胞过程，包括纤维蛋白溶解，血管生成，凋亡，炎症，转移和病毒发病机理。在这里，我们通过对典型家族成员纤溶酶原激活物抑制剂2（PAI-2）的P8残基进行饱和诱变，研究了丝氨酸蛋白酶抑制蛋白（serpins）独特的捕鼠抑制机制。大量研究提出了P8残基在裂解反应中心环（RCL）的有效插入和稳定中的重要作用，这是丝氨酸蛋白酶抑制蛋白抑制机制中的关键事件。尽管观察到了对P8取代的高度耐受性，但该残基对于抑制PAI-2蛋白酶靶尿纤溶酶原激活剂（尿激酶，uPA）的重要性得到了证实。在19种可能的PAI-2 P8突变体中，有16种在野生型P8 Thr物种数量级内显示抑制活性。确定了具有P8 Met或Asp突变的PAI-2和RCL模仿肽之间的复合物的晶体结构，与野生型复合物的结构比较证实了S8口袋容纳不同侧链的能力。这些数据表明，P8残基的身份不是有效RCL插入的决定因素，并为酶结构内关键残基的功能可塑性提供了进一步的证据。观察到的PAI-2 P8突变体活性与一系列理化，进化和热力学预测指标之间的相关性很差，突显了预测蛋白质变体分子表型的现有方法的实际局限性。

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