The Z type variation of human alpha 1-antitrypsin causes a protein folding defect.
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.
Yu
M H
MH
Genetic Engineering Research Institute, Korea Institute of Science and Technology, Yusong, Taejon.
Lee
K N
KN
Kim
J
J
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D003460:Crystallization; D004586:Electrophoresis / Q000379:methods; D004646:Emphysema / Q000209:etiology*; D006801:Humans; D008099:Liver / Q000503:physiopathology; D009154:Mutation; D010196:Pancreatic Elastase / Q000378:metabolism; D017510:Protein Folding; D011868:Radioisotopes; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D000596:Amino Acids; D011868:Radioisotopes; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase