ArticleBioscience reports2013
Reactive centre loop mutants of α-1-antitrypsin reveal position-specific effects on intermediate formation along the polymerization pathway.
Article in Bioscience reports, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
19 citing papers in PubMed, 29 citations in OpenAlex.
- Functional and clinical significance of novel SERPINA1 variants on alpha-1 antitrypsin deficiency.Respiratory research · 2026Article
- The Role of Alpha-1 Antitrypsin in the Pathophysiology and Treatment of Inflammatory Lung Diseases.Journal of inflammation research · 2026Review
- 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
- Probing of the reactive center loop region of alpha-1-antitrypsin by mutagenesis predicts new type-2 dysfunctional variants.Cellular and molecular life sciences : CMLS · 2023Article
- Scaling Concepts in Serpin Polymer Physics.Materials (Basel, Switzerland) · 2021Article
- The molecular species responsible for αThe FEBS journal · 2021Article
- Development of a small molecule that corrects misfolding and increases secretion of Z αEMBO molecular medicine · 2021Article
- High-resolution ex vivo NMR spectroscopy of human Z αNature communications · 2020Article
- The structural basis for Z αScience advances · 2020Article
- Engineering the serpin αProtein science : a publication of the Protein Society · 2020Review
- Characterisation of a type II functionally-deficient variant of alpha-1-antitrypsin discovered in the general population.PloS one · 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
- 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
- Characterising the association of latency with α(1)-antitrypsin polymerisation using a novel monoclonal antibody.The international journal of biochemistry & cell biology · 2015Article
- Altered native stability is the dominant basis for susceptibility of α1-antitrypsin mutants to polymerization.The Biochemical journal · 2014Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The common severe Z mutation (E342K) of α1-antitrypsin forms intracellular polymers that are associated with liver cirrhosis. The native fold of this protein is well-established and models have been proposed from crystallographic and biophysical data for the stable inter-molecular configuration that terminates the polymerization pathway. Despite these molecular 'snapshots', the details of the transition between monomer and polymer remain only partially understood. We surveyed the RCL (reactive centre loop) of α1-antitrypsin to identify sites important for progression, through intermediate states, to polymer. Mutations at P14P12 and P4, but not P10P8 or P2P1', resulted in a decrease in detectable polymer in a cell model that recapitulates the intracellular polymerization of the Z variant, consistent with polymerization from a near-native conformation. We have developed a FRET (Förster resonance energy transfer)-based assay to monitor polymerization in small sample volumes. An in vitro assessment revealed the position-specific effects on the unimolecular and multimolecular phases of polymerization: the P14P12 region self-inserts early during activation, while the interaction between P6P4 and β-sheet A presents a kinetic barrier late in the polymerization pathway. Correspondingly, mutations at P6P4, but not P14P12, yield an increase in the overall apparent activation energy of association from ~360 to 550 kJ mol(-1).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.