The Z mutation alters the global structural dynamics of α1-antitrypsin

PLoS One. 2014 Sep 2;9(9):e102617. doi: 10.1371/journal.pone.0102617. eCollection 2014.


α1-Antitrypsin (α1AT) deficiency, the most common serpinopathy, results in both emphysema and liver disease. Over 90% of all clinical cases of α1AT deficiency are caused by the Z variant in which Glu342, located at the top of s5A, is replaced by a Lys which results in polymerization both in vivo and in vitro. The Glu342Lys mutation removes a salt bridge and a hydrogen bond but does not effect the thermodynamic stability of Z α1AT compared to the wild type protein, M α1AT, and so it is unclear why Z α1AT has an increased polymerization propensity. We speculated that the loss of these interactions would make the native state of Z α1AT more dynamic than M α1AT and that this change renders the protein more polymerization prone. We have used hydrogen/deuterium exchange combined with mass spectrometry (HXMS) to determine the structural and dynamic differences between native Z and M α1AT to reveal the molecular basis of Z α1AT polymerization. Our HXMS data shows that the Z mutation significantly perturbs the region around the site of mutation. Strikingly the Z mutation also alters the dynamics of regions distant to the mutation such as the B, D and I helices and specific regions of each β-sheet. These changes in global dynamics may lead to an increase in the likelihood of Z α1AT sampling a polymerogenic structure thereby causing disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Deuterium Exchange Measurement
  • Humans
  • Kinetics
  • Molecular Sequence Data
  • Mutation / genetics*
  • Native Polyacrylamide Gel Electrophoresis
  • Peptides / chemistry
  • Tandem Mass Spectrometry
  • Time Factors
  • alpha 1-Antitrypsin / chemistry*
  • alpha 1-Antitrypsin / genetics*


  • Peptides
  • alpha 1-Antitrypsin

Grant support

This work was funded by the The National Health and Medical Research Council (NHMRC) (Aus). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.