Defining the mechanism of polymerization in the serpinopathies
Defining the mechanism of polymerization in the serpinopathies
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DOI：
10.1073/pnas.1004785107
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发表时间：
2010-10-05
影响因子：
11.1
通讯作者：
Lomas, David A.
中科院分区：
文献类型：
--
作者：
Ekeowa, Ugo I.;Freeke, Joanna;Lomas, David A.
丝氨酸蛋白酶抑制剂病是由丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）超家族成员的突变体有序聚合引起的。这些聚合物被保留在合成细胞内，在那里它们引起毒性的功能增益。丝氨酸蛋白酶蛋白病的例子是与肝硬化相关的α（1）-抗胰蛋白酶的常见严重Z突变体形成的包涵体。关于Serpin聚合的途径和引起疾病的致病聚合物的结构存在相当大的争议。我们已经使用合成肽，有限的蛋白水解，单克隆抗体，和离子迁移率-质谱来表征由Z α（1）-抗胰蛋白酶形成的聚合中间体和病理聚合物。我们的数据是最好的解释模型，其中聚合物形成通过一个单一的中间体，并与反应中心环β-片层A连接。我们的数据与最近的模型不兼容，在该模型中，聚合物通过反应中心环和链5A的β-发夹连接。了解丝氨酸蛋白酶抑制剂聚合物的结构对于合理的药物设计策略是必不可少的，这些策略旨在阻断聚合，从而治疗α（1）-抗胰蛋白酶缺乏症和丝氨酸蛋白酶抑制剂病。
The serpinopathies result from the ordered polymerization of mutants of members of the serine proteinase inhibitor (serpin) superfamily. These polymers are retained within the cell of synthesis where they cause a toxic gain of function. The serpinopathies are exemplified by inclusions that form with the common severe Z mutant of alpha(1)-antitrypsin that are associated with liver cirrhosis. There is considerable controversy as to the pathway of serpin polymerization and the structure of pathogenic polymers that cause disease. We have used synthetic peptides, limited proteolysis, monoclonal antibodies, and ion mobility-mass spectrometry to characterize the polymerogenic intermediate and pathological polymers formed by Z alpha(1)-antitrypsin. Our data are best explained by a model in which polymers form through a single intermediate and with a reactive center loop-beta-sheet A linkage. Our data are not compatible with the recent model in which polymers are linked by a beta-hairpin of the reactive center loop and strand 5A. Understanding the structure of the serpin polymer is essential for rational drug design strategies that aim to block polymerization and so treat alpha(1)-antitrypsin deficiency and the serpinopathies.