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

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