ArticleThe FEBS journal2017
The pathological Trento variant of alpha-1-antitrypsin (E75V) shows nonclassical behaviour during polymerization.
Article in The FEBS journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 30 citations in OpenAlex.
- Susceptibility of alpha-1 antitrypsin deficiency variants to polymer-blocking therapy.JCI insight · 2025Article
- Top-Down Ion Mobility Mass Spectrometry Reveals a Disease Associated Conformational Ensemble of Alpha-1-antitrypsin.Journal of the American Chemical Society · 2025Article
- High-resolution characterization of ex vivo AAT polymers by solution-state NMR spectroscopy.Science advances · 2025Article
- α‑1 Antitrypsin is a potential target of inflammation and immunomodulation (Review).Molecular medicine reports · 2025Review
- Spatial covariance reveals isothiocyanate natural products adjust redox stress to restore function in alpha-1-antitrypsin deficiency.Cell reports. Medicine · 2025Article
- Characterization of Novel Alpha-1-Antitrypsin Coding Variants in a Mammalian Cellular Model.Methods in molecular biology (Clifton, N.J.) · 2024Article
- The conformational landscape of a serpin N-terminal subdomain facilitates folding and in-cell quality control.bioRxiv : the preprint server for biology · 2023Article
- Novel SERPINA1 Alleles Identified through a Large Alpha-1 Antitrypsin Deficiency Screening Program and Review of Known Variants.Chronic obstructive pulmonary diseases (Miami, Fla.) · 2023Article
- Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis.Cell chemical biology · 2023Article
- Structural characterization and conformational dynamics of alpha-1 antitrypsin pathogenic variants causing alpha-1-antitrypsin deficiency.Frontiers in molecular biosciences · 2022Article
- Proteomic and molecular dynamic investigations of PTM-induced structural fluctuations in breast and ovarian cancer.Scientific reports · 2021Observational
- The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant.International journal of molecular sciences · 2021Article
- Scaling Concepts in Serpin Polymer Physics.Materials (Basel, Switzerland) · 2021Article
- The molecular species responsible for αThe FEBS journal · 2021Article
- N-Glycosylation as a Tool to Study Antithrombin Secretion, Conformation, and Function.International journal of molecular sciences · 2021Article
- Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein.International journal of molecular sciences · 2020Review
- The structural basis for Z αScience advances · 2020Article
- Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin.JCI insight · 2020Article
- Leveraging Population Genomics for Individualized Correction of the Hallmarks of Alpha-1 Antitrypsin Deficiency.Chronic obstructive pulmonary diseases (Miami, Fla.) · 2020Review
- Characterisation of a type II functionally-deficient variant of alpha-1-antitrypsin discovered in the general population.PloS one · 2019Article
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Severe alpha-1-antitrypsin deficiency (AATD) is most frequently associated with the alpha-1-antitrypsin (AAT) Z variant (E342K). ZZ homozygotes exhibit accumulation of AAT as polymers in the endoplasmic reticulum of hepatocytes. This protein deposition can lead to liver disease, with the resulting low circulating levels of AAT predisposing to early-onset emphysema due to dysregulation of elastinolytic activity in the lungs. An increasing number of rare AAT alleles have been identified in patients with severe AATD, typically in combination with the Z allele. Here we report a new mutation (E75V) in a patient with severe plasma deficiency, which we designate Trento. In contrast to the Z mutant, Trento AAT was secreted efficiently when expressed in cellular models but showed compromised conformational stability. Polyacrylamide gel electrophoresis (PAGE) and ELISA-based analyses of the secreted protein revealed the presence of oligomeric species with electrophoretic and immunorecognition profiles different from those of Z and S (E264V) AAT polymers, including reduced recognition by conformational monoclonal antibodies 2C1 and 4B12. This altered recognition was not due to direct effects on the epitope of the 2C1 monoclonal antibody which we localized between helices E and F. Structural analyses indicate the likely basis for polymer formation is the loss of a highly conserved stabilizing interaction between helix C and the posthelix I loop. These results highlight this region as important for maintaining native state stability and, when compromised, results in the formation of pathological polymers that are different from those produced by Z and S AAT.
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