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

MH Yu, KN Lee, J Kim - Nature structural biology, 1995 - nature.com
MH Yu, KN Lee, J Kim
Nature structural biology, 1995nature.com
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 …
Abstract
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.
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