ArticleThe Biochemical journal2014
Altered native stability is the dominant basis for susceptibility of α1-antitrypsin mutants to polymerization.
Article in The Biochemical journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 28 citations in OpenAlex.
- Z variant heterozygosity in alpha-1 antitrypsin deficiency: disease risk and treatment implications.Orphanet journal of rare diseases · 2026Article
- The mechanism of pathogenic αProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Susceptibility of alpha-1 antitrypsin deficiency variants to polymer-blocking therapy.JCI insight · 2025Article
- A novel pathological mutant reveals the role of torsional flexibility in the serpin breach in adoption of an aggregation-prone intermediate.The FEBS journal · 2024Article
- Recommendations for the diagnosis and treatment of alpha-1 antitrypsin deficiency.Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia · 2024Article
- Utility of the Serum Protein Electrophoresis in the Opportunistic Screening for the Deficiency of Alpha-1 Antitrypsin.Diagnostics (Basel, Switzerland) · 2023Article
- Quantitative interrogation of protein co-aggregation using multi-color fluorogenic protein aggregation sensors.Chemical science · 2021Article
- Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes.Developmental cell · 2021Article
- Development of a small molecule that corrects misfolding and increases secretion of Z αEMBO molecular medicine · 2021Article
- Alpha-1 Antitrypsin Z Variant (AAT PI*Z) as a Risk Factor for Intrahepatic Cholestasis of Pregnancy.Frontiers in genetics · 2021Article
- The structural basis for Z αScience advances · 2020Article
- Engineering the serpin αProtein science : a publication of the Protein Society · 2020Review
- Calcium signalling in mammalian cell lines expressing wild type and mutant human α1-Antitrypsin.Scientific reports · 2019Article
- Probing the folding pathway of a consensus serpin using single tryptophan mutants.Scientific reports · 2018Article
- The pathological Trento variant of alpha-1-antitrypsin (E75V) shows nonclassical behaviour during polymerization.The FEBS journal · 2017Article
- An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behaviour.The Biochemical journal · 2016Article
- Deficiency Mutations of Alpha-1 Antitrypsin. Effects on Folding, Function, and Polymerization.American journal of respiratory cell and molecular biology · 2016Article
- Interactions between N-linked glycosylation and polymerisation of neuroserpin within the endoplasmic reticulum.The FEBS journal · 2015Article
- An integrative approach combining ion mobility mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of α1 -antitrypsin upon ligand binding.Protein science : a publication of the Protein Society · 2015Article
- An antibody raised against a pathogenic serpin variant induces mutant-like behaviour in the wild-type protein.The Biochemical journal · 2015Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Serpins are protease inhibitors whose most stable state is achieved upon transition of a central 5-stranded β-sheet to a 6-stranded form. Mutations, low pH, denaturants and elevated temperatures promote this transition, which can result in a growing polymer chain of inactive molecules. Different types of polymer are possible, but, experimentally only heat has been shown to generate polymers in vitro consistent with ex vivo pathological specimens. Many mutations that alter the rate of heat-induced polymerization have been described, but interpretation is problematic because discrimination is lacking between the effect of global changes in native stability and specific effects on structural mechanism. We show that the temperature midpoint (Tm) of thermal denaturation reflects the transition of α1-antitrypsin to the polymerization intermediate, and determine the relationship with fixed-temperature polymerization half-times (t0.5) in the presence of stabilizing additives [TMAO (trimethylamine N-oxide), sucrose and sodium sulfate], point mutations and disulfide bonds. Combined with a retrospective analysis of 31 mutants characterized in the literature, the results of the present study show that global changes to native state stability are the predominant basis for the effects of mutations and osmolytes on heat-induced polymerization, summarized by the equation: ln(t0.5,mutant/t0.5,wild-type)=0.34×ΔTm. It is deviations from this relationship that hold key information about the polymerization process.
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