ArticleJCI insight2020
Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 25 citations in OpenAlex.
- Polymerized Z-α-1 antitrypsin leads to lung injury in a murine model of emphysema.JCI insight · 2026Article
- The mechanism of pathogenic αProceedings of the National Academy of Sciences of the United States of America · 2025Article
- High-resolution characterization of ex vivo AAT polymers by solution-state NMR spectroscopy.Science advances · 2025Article
- Identification of an exosite at the neutrophil elastase/alpha-1-antitrypsin interface.The FEBS journal · 2025Article
- Association of circulating Z-polymer with adverse clinical outcomes and liver fibrosis in adults with alpha-1 antitrypsin deficiency.United European gastroenterology journal · 2024Article
- 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
- Characterization of Novel Alpha-1-Antitrypsin Coding Variants in a Mammalian Cellular Model.Methods in molecular biology (Clifton, N.J.) · 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
- Human iPSC-Derived 3D Hepatic Organoids in a Miniaturized Dynamic Culture System.Biomedicines · 2023Article
- Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis.Cell chemical biology · 2023Article
- Liver gene therapy: The magic bullet for the sick lung.Molecular therapy. Methods & clinical development · 2022Article
- Protein Misfolding and Aggregation: The Relatedness between Parkinson's Disease and Hepatic Endoplasmic Reticulum Storage Disorders.International journal of molecular sciences · 2021Review
- Neuroserpin: structure, function, physiology and pathology.Cellular and molecular life sciences : CMLS · 2021Review
- The Recruitment-Secretory Block ("R-SB") Phenomenon and Endoplasmic Reticulum Storage Diseases.International journal of molecular sciences · 2021Review
- 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
- The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain.International journal of molecular sciences · 2021Review
- Development of a small molecule that corrects misfolding and increases secretion of Z αEMBO molecular medicine · 2021Article
- Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein.International journal of molecular sciences · 2020Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 4 countries.
Funding
Abstract
The α-1-antitrypsin (or alpha-1-antitrypsin, A1AT) Z variant is the primary cause of severe A1AT deficiency and forms polymeric chains that aggregate in the endoplasmic reticulum of hepatocytes. Around 2%-5% of Europeans are heterozygous for the Z and WT M allele, and there is evidence of increased risk of liver disease when compared with MM A1AT individuals. We have shown that Z and M A1AT can copolymerize in cell models, but there has been no direct observation of heteropolymer formation in vivo. To this end, we developed a monoclonal antibody (mAb2H2) that specifically binds to M in preference to Z A1AT, localized its epitope using crystallography to a region perturbed by the Z (Glu342Lys) substitution, and used Fab fragments to label polymers isolated from an MZ heterozygote liver explant. Glu342 is critical to the affinity of mAb2H2, since it also recognized the mild S-deficiency variant (Glu264Val) present in circulating polymers from SZ heterozygotes. Negative-stain electron microscopy of the Fab2H2-labeled liver polymers revealed that M comprises around 6% of the polymer subunits in the MZ liver sample. These data demonstrate that Z A1AT can form heteropolymers with polymerization-inert variants in vivo with implications for liver disease in heterozygous individuals.
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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.