Carrell R W, Stein P E
Department of Haematology, University of Cambridge, UK.
Biol Chem Hoppe Seyler. 1996 Jan;377(1):1-17. doi: 10.1515/bchm3.1996.377.1.1.
The serpins illustrate the way in which the study of a protein family as a whole can clarify the functions of its individual members. Although the individual serpins have become remarkably diversified by evolution they all share a common structural pathology. We have previously shown how plotting of the dysfunctional natural mutations of the serpins on a template structure defines the domains controlling the mobility of the reactive centre loop of the molecule. Here we compare these natural mutations with reciprocal mutations in recombinants that restore the inhibitory stability of a labile member of the family, plasminogen activator inhibitor-1 (PAI-1). The combined results emphasise the critical part played by residues involved in the sliding movement that opens the A-sheet to allow reactive loop insertion. It is concluded that changes in these residues provide the prime explanation for the ready conversion of PAI-1 to the inactive latent state. The consistency of the overall results gives confidence in predicting the likely consequences of mutations in individual serpins. In particular the two common polymorphic mutations present in human angiotensinogen are likely to affect molecular stability and hence may be contributory factors to the observed association with vascular disease.
丝氨酸蛋白酶抑制剂说明了将一个蛋白质家族作为一个整体进行研究能够阐明其各个成员功能的方式。尽管丝氨酸蛋白酶抑制剂的各个成员在进化过程中已经显著分化，但它们都具有共同的结构病理学特征。我们之前已经表明，将丝氨酸蛋白酶抑制剂的功能失调自然突变绘制在模板结构上，能够确定控制分子反应中心环移动性的结构域。在此，我们将这些自然突变与重组体中的反向突变进行比较，这些重组体恢复了该家族中一个不稳定成员——纤溶酶原激活物抑制剂1（PAI-1）的抑制稳定性。综合结果强调了参与滑动运动的残基所起的关键作用，这种滑动运动会打开A片层以允许反应环插入。得出的结论是，这些残基的变化为PAI-1易于转变为无活性的潜伏状态提供了主要解释。总体结果的一致性让我们有信心预测单个丝氨酸蛋白酶抑制剂中突变可能产生的后果。特别是人类血管紧张素原中存在的两种常见多态性突变可能会影响分子稳定性，因此可能是与血管疾病关联的促成因素。
