Retarded protein folding of deficient human alpha 1-antitrypsin D256V and L41P variants

Protein Sci. 2004 Mar;13(3):694-702. doi: 10.1110/ps.03356604. Epub 2004 Feb 6.


alpha(1)-Antitrypsin is the most abundant protease inhibitor in plasma and is the archetype of the serine protease inhibitor superfamily. Genetic variants of human alpha(1)-antitrypsin are associated with early-onset emphysema and liver cirrhosis. However, the detailed molecular mechanism for the pathogenicity of most variant alpha(1)-antitrypsin molecules is not known. Here we examined the structural basis of a dozen deficient alpha(1)-antitrypsin variants. Unlike most alpha(1)-antitrypsin variants, which were unstable, D256V and L41P variants exhibited extremely retarded protein folding as compared with the wild-type molecule. Once folded, however, the stability and inhibitory activity of these variant proteins were comparable to those of the wild-type molecule. Retarded protein folding may promote protein aggregation by allowing the accumulation of aggregation-prone folding intermediates. Repeated observations of retarded protein folding indicate that it is an important mechanism causing alpha(1)-antitrypsin deficiency by variant molecules, which have to fold into the metastable native form to be functional.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circular Dichroism
  • Electrophoresis, Polyacrylamide Gel
  • Hot Temperature
  • Humans
  • Leukocyte Elastase / antagonists & inhibitors
  • Leukocyte Elastase / metabolism
  • Mutagenesis, Site-Directed
  • Mutation, Missense / genetics*
  • Pancreatic Elastase / antagonists & inhibitors
  • Pancreatic Elastase / metabolism
  • Protein Conformation
  • Protein Denaturation
  • Protein Folding*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Spectrometry, Fluorescence
  • Swine
  • Thermodynamics
  • Time Factors
  • Urea / chemistry
  • alpha 1-Antitrypsin / chemistry*
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / metabolism


  • Recombinant Proteins
  • alpha 1-Antitrypsin
  • Urea
  • Pancreatic Elastase
  • Leukocyte Elastase