ArticleJournal of the American Chemical Society2025
Top-Down Ion Mobility Mass Spectrometry Reveals a Disease Associated Conformational Ensemble of Alpha-1-antitrypsin.
Article in Journal of the American Chemical Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- The mechanism of pathogenic αProceedings of the National Academy of Sciences of the United States of America · 2025Article
- A cure for alpha-1? Novel therapeutics in alpha-1 antitrypsin deficiency.The European respiratory journal · 2025Article
- Susceptibility of alpha-1 antitrypsin deficiency variants to polymer-blocking therapy.JCI insight · 2025Article
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Authors and funding
6 authors.
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Abstract
Mutants of members of the serpin superfamily can undergo nonamyloid aggregation to form polymeric chains that are associated with disease. This is typified by Z alpha-1-antitrypsin (Glu342Lys) that accumulates as polymers within hepatocytes to cause cirrhosis. We have used ion mobility mass spectrometry and electron-capture dissociation to directly observe and characterize novel intermediates formed during polymerization. Our data are congruent with an ensemble of conformations that are monomeric but maintained in a partially misfolded metastable state in which ∼12% of the molecule at the C-terminus is displaced. The application of these techniques to Z alpha-1-antitrypsin polymers isolated from human liver revealed a molecular species most consistent with a polymer mediated by an intermolecular C-terminal domain insertion. These findings establish a previously unobserved progression of pathogenic structural changes and thereby extend the mechanism of alpha-1-antitrypsin polymerization. They additionally demonstrate the strengths of native top-down ion mobility mass spectrometry in characterizing misfolding intermediates and proteins isolated from human tissue.
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