Dynamic local unfolding in the serpin [alpha]-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 α-1 antitrypsin (α 1 AT) and show how...

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Bibliographic Details
Published inNature structural & molecular biology Vol. 18; no. 2; p. 222
Main Authors Krishnan, Beena, Gierasch, Lila M
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group 01.02.2011
Subjects
Crystal structure
Molecular biology
Mutation
Plasticity
Protease inhibitors
Protein folding
Proteinase inhibitors
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Summary: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 α-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 sampling of high risk conformations on a dynamic energy landscape. [PUBLICATION ABSTRACT]
ISSN:1545-9993
1545-9985
DOI:10.1038/nsmb.1976