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Cellular responses in the aetiology of COPD
P117 3D cryo-electron microscopic analysis of the disease mechanism of α1-antitrypsin deficiency
  1. B Gooptu1,
  2. Y Chaban1,
  3. J A Irving2,
  4. D K Clare1,
  5. D A Lomas2,
  6. E Orlova1,
  7. H R Saibil1
  1. 1Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London, UK
  2. 2Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK

Abstract

α1-antitrypsin deficiency is characterised by predispositions to liver disease and severe, early-onset emphysema. It is caused by point mutations that destabilise the molecular structure of α1-antitrypsin, leading it to self-associate into chains known as polymers. Polymerisation abolishes the antiprotease activity of α1-antitrypsin and causes circulating deficiency of the protein. These loss-of-function effects result in dysregulated elastase activity within the lung parenchyma. In addition, polymerisation has pro-inflammatory gain-of-function effects that must be mediated through the structural characteristics of the polymer itself. It is therefore important to understand the structure of the α1-antitrypsin polymer to identify targets for drug design. We have used cryo-electron microscopy, single particle reconstruction techniques to study α1-antitrypsin polymers. Analysis of the 3D arrangement of α1-antitrypsin molecules within the directly observed polymer chain allows us to evaluate current competing models of polymer assembly.

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