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首页> 外文期刊>The FEBS journal >The molecular species responsible for alpha(1)-antitrypsin deficiency are suppressed by a small molecule chaperone
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The molecular species responsible for alpha(1)-antitrypsin deficiency are suppressed by a small molecule chaperone

机译：负责α（1） - 丙烯蛋白缺乏的分子物种被小分子伴侣抑制

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摘要

The formation of ordered Z (Glu342Lys) alpha(1)-antitrypsin polymers in hepatocytes is central to liver disease in alpha(1)-antitrypsin deficiency. In vitro experiments have identified an intermediate conformational state (M*) that precedes polymer formation, but this has yet to be identified in vivo. Moreover, the mechanism of polymer formation and their fate in cells have been incompletely characterised. We have used cell models of disease in conjunction with conformation-selective monoclonal antibodies and a small molecule inhibitor of polymerisation to define the dynamics of polymer formation, accumulation and secretion. Pulse-chase experiments demonstrate that Z alpha(1)-antitrypsin accumulates as short-chain polymers that partition with soluble cellular components and are partially secreted by cells. These precede the formation of larger, insoluble polymers with a longer half-life (10.9 +/- 1.7 h and 20.9 +/- 7.4 h for soluble and insoluble polymers, respectively). The M* intermediate (or a by-product thereof) was identified in the cells by a conformation-specific monoclonal antibody. This was completely abrogated by treatment with the small molecule, which also blocked the formation of intracellular polymers. These data allow us to conclude that the M* conformation is central to polymerisation of Z alpha(1)-antitrypsin in vivo; preventing its accumulation represents a tractable approach for pharmacological treatment of this condition; polymers are partially secreted; and polymers exist as two distinct populations in cells whose different dynamics have likely consequences for the aetiology of the disease.
机译：肝细胞中有序Z（Glu342Lys）α（1）-抗胰蛋白酶聚合物的形成是α（1）-抗胰蛋白酶缺乏症肝脏疾病的核心。体外实验已经确定了聚合物形成之前的一种中间构象状态（M*），但这尚未在体内确定。此外，聚合物的形成机制及其在细胞中的命运尚未完全阐明。我们使用了疾病的细胞模型，结合构象选择性单克隆抗体和小分子聚合抑制剂来定义聚合物形成、积累和分泌的动力学。脉冲追踪实验表明，Z-α（1）-抗胰蛋白酶以短链聚合物的形式聚集，与可溶性细胞成分相分离，部分由细胞分泌。在形成更大的、半衰期更长的不溶性聚合物之前（可溶和不溶性聚合物分别为10.9+/-1.7小时和20.9+/-7.4小时）。通过构象特异性单克隆抗体在细胞中鉴定M*中间体（或其副产物）。小分子治疗完全消除了这一点，同时也阻止了细胞内聚合物的形成。这些数据使我们得出结论，M*构象是Z-α（1）-抗胰蛋白酶在体内聚合的中心；防止其积聚是药物治疗这种疾病的一种可行方法；聚合物部分分泌；聚合物作为两个不同的群体存在于细胞中，其不同的动力学可能会对疾病的病因产生影响。

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