The Z type variation of human alpha 1-antitrypsin causes a protein folding defect

Nat Struct Biol. 1995 May;2(5):363-7. doi: 10.1038/nsb0595-363.


Emphysema is often associated with the Z type mutation of alpha 1-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 alpha 1-antitrypsin is extremely slow. Once folded, however, the native Z protein shows substantial stability towards urea and incubation at 37 degrees 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Crystallization
  • Electrophoresis / methods
  • Emphysema / etiology*
  • Humans
  • Liver / physiopathology
  • Mutation
  • Pancreatic Elastase / metabolism
  • Protein Folding*
  • Radioisotopes
  • alpha 1-Antitrypsin / chemistry*
  • alpha 1-Antitrypsin / genetics*
  • alpha 1-Antitrypsin / metabolism


  • Amino Acids
  • Radioisotopes
  • alpha 1-Antitrypsin
  • Pancreatic Elastase