Dynamic local unfolding in the serpin α-1 antitrypsin provides a mechanism for loop insertion and polymerization

The conformational plasticity of serine protease inhibitors (serpins) underlies both their activities as protease inhibitors and their susceptibility to pathogenic misfolding and aggregation. Here, we structurally characterize a sheet-opened state of the serpin alpha-1 antitrypsin (alpha(1)AT) and show how local unfolding allows functionally essential strand insertion. Mutations in alpha(1)AT that cause polymerization-induced serpinopathies map to the labile region, suggesting that the evolution of serpin function required sampling of high risk conformations on a dynamic energy landscape.