The Z type variation of human α₁-antitrypsin causes a protein folding defect

Emphysema is often associated with the Z type mutation of α1- antitrypsin, which causes aggregation of the molecule in the liver and consequent plasma deficiency. The aggregation appears to be due to loop- sheet polymerization, although why the mutant protein polymerizes in vivo is unclear. Here we show that, unlike wild type antitrypsin, which folds in minutes, the folding of Z type α1-antitrypsin is extremely slow. Once folded, however, the native Z protein shows substantial stability towards urea and incubation at 37 °C. The folding defect in Z antitrypsin leads to accumulation of an intermediate and it is the intermediate rather than the native protein which has a high tendency to aggregate.ope