Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 18, Issue 2, Pages 222-U288Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1976
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Funding
- US National Institutes of Health [OD-00045]
- Alpha-1 Foundation
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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.
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