Molecular analysis of alpha-1-Antitrypsin misfolding: a cause of alpha-1-antitrypsin deficiency

抗胰蛋白酶缺乏症的发生率约为1 / 1800。它是儿童肝脏疾病和成人肺部疾病肺气肿最常见的遗传原因。抗胰蛋白酶在肝脏中产生并分泌到血液循环中。它的主要作用是抑制攻击肺组织的降解酶弹性酶。抗胰蛋白酶缺乏导致弹性酶活性失控，破坏肺组织从而引起肺气肿。这种缺乏通常是由抗胰蛋白酶无法进入循环引起的。这是由于抗胰蛋白酶分子内的突变导致蛋白质采用不正确的三维结构。这导致蛋白质在肝脏内形成长链，进而损害肝细胞。目前还没有针对抗胰蛋白酶缺乏症的特异性治疗方法，这在一定程度上反映了我们对这种疾病的分子基础缺乏了解。这个项目检查突变对抗胰蛋白酶折叠的影响，以便我们能够了解这些长蛋白链是如何形成的。使用一系列生化技术，我们将监测正常和异常蛋白质折叠时的结构变化，以确定突变是如何破坏这一过程的。这些数据将使我们能够开始合理设计抑制剂，防止长链的形成，我们希望这将有助于治疗抗胰蛋白酶缺乏症患者。这种对抗胰蛋白酶缺乏症的进一步了解也可能有利于发生类似蛋白质错误折叠的其他疾病过程，如淀粉样蛋白和朊病毒疾病。

Antitrypsin deficiency occurs in approximately 1 in 1800 live births. It is the most common genetic cause of liver disease in children and the debilitating lung disease emphysema in adults. Antitrypsin is produced in the liver and secreted into the circulation. Its primary role is to inhibit the degradative enzyme elastase which attacks the tissues of the lung. A deficiency in Antitrypsin leads to uncontrolled elastase activity which destroys the lung tissue so causing emphysema. The deficiency is commonly caused by Antitrypsin being unable to enter the circulation. This is due to mutations within the Antitrypsin molecule which cause the protein to adopt an incorrect three-dimensional structure. This causes the protein to form long chains within the liver, which in turn damage the liver cell. There are no specific treatments for Antitrypsin deficiency, this partly reflects our lack of understanding of the molecular basis of the disease. This project examines the effects of the mutations upon the folding of Antitrypsin so that we can understand how these long protein chains form. Using a range of biochemical techniques we will monitor structural changes within the normal and abnormal proteins as they fold to determine how the mutations disrupt the process. These data will allow us to begin to rationally design inhibitors which will prevent the formation of the long chains, which we hope will aid in the treatment of patients with Antitrypsin deficiency. This increased understanding of Antitrypsin deficiency may also benefit other disease processes where similar protein misfolding occurs such as amyloid and prion diseases.