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

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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Yu, MH., Lee, K. & Kim, J. The Z type variation of human α1-antitrypsin causes a protein folding defect. Nat Struct Mol Biol 2, 363–367 (1995). https://doi.org/10.1038/nsb0595-363

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