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

点击翻译按钮获取中文摘要

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.