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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