-antitrypsin misfolding

We were all taught that proteins have to fold correctly to be active and that the primary sequence of amino acids acts as the ’blueprint‘ for successful, productive folding. in recent years, we have also learnt how sensitive that blueprint is to change. For example, a single amino-acid change in the protein sequence, or a subtle change in temperature at which folding takes place, can lead to the formation and accumulation of non-native species, which have a tendency to self-associate and deposit in and around tissues, thereby triggering disease. to understand protein misfolding and its links with disease, we need information about the structures of all the key players and their relationships with each other. this has proven exceptionally challenging due to the transient nature of many of the species involved and the heterogeneity of the final misfolded product. For one misfolding disorder, α1-antitrypsin deficiency—a devastating disease that affects approximately 1 in 2,500 individuals—we are a step closer to characterizing all of the main culprits. in this issue of EMBo reports, Huntington and colleagues present the X-ray crystal structure of an α1-antitrypsin trimer that sheds light on the structure of a potentially pathogenic form of α1-antitrypsin and provides new insights into the molecular mechanism of α1-antitrypsin deficiency (yamasaki et al, 2011). attempts to understand the molecular basis for α1-antitrypsin deficiency began in 1963 when laurell & Eriksson noticed its absence from the serum of a cohort of patients with obs tructive lung disease (laurell & Eriksson, 1963). Sharp and co-workers subsequently described periodic acid Schiff-positive inclusions of α1-antitrypsin within hepatocytes of α1-antitrypsin-deficient patients (Sharp et al, 1969). these two findings linked the major clinical outcomes of the disease. α1-antitrypsin inhibits elastase in the lower respiratory tract and, therefore, a plasma deficiency leads to early onset emphysema due to uncontrolled elastase activity. the aggregation of α1-antitrypsin at its site of production—the hepatocyte—leads to liver damage and cirrhosis. in the early 1990s, elegant work by lomas and colleagues revealed that the key molecular event leading to the deficiency was the misfolding and formation of α1-antitrypsin polymers within the endoplasmic reticulum of hepatocytes (lomas et al, 1992). α1-antitrypsin, like all members of the serpin superfamily, is a large single-domain protein consisting of 394 amino acids that fold into three β-sheets surrounded by nine α-helices (Fig 1; Elliott et al, 2000). protruding from the core structure is the flexible reactive centre loop, containing the scissile bond that dictates the inhibitory specificity of a serpin. Similar to all serpins, α1-antitrypsin undergoes a marked conformational change to inhibit proteinases, which involves the insertion of the reactive centre loop into the middle of β-sheet a. this conformational change is possible because the native state of the serpin superfamily is metastable. However, the instability of the native state of α1-antitrypsin makes it extremely susceptible to misfolding and polymeri zation, which results in the formation of more thermodynamically stable conformations. the most common mutation that causes polymerization in α1-antitrypsin is the z mutation (glu342lys), which is present in approximately 4% of northern Europeans. this mutation s4A/s5A swap