Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin
| Autor: | Riccardo Ronzoni, Nina Heyer-Chauhan, Elena Miranda, David A. Lomas, James A. Irving, Mattia Laffranchi, Annamaria Fra, Juan Pérez, Emma L. K. Elliston, Mark L. Brantly, Alistair M. Jagger |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Liver Cirrhosis
0301 basic medicine Protein Conformation medicine.drug_class Alpha (ethology) Diagnostics Genetic diseases Genetics Hepatology Structural biology Endoplasmic Reticulum Monoclonal antibody Epitope Epitopes Protein Aggregates 03 medical and health sciences Liver disease 0302 clinical medicine In vivo Catalytic Domain alpha 1-Antitrypsin Deficiency medicine Humans Allele Alleles Crystallography Chemistry Endoplasmic reticulum Genetic Variation Heterozygote advantage General Medicine medicine.disease Molecular biology 3. Good health 030104 developmental biology Liver alpha 1-Antitrypsin 030220 oncology & carcinogenesis Hepatocytes Research Article |
| Zdroj: | 'JCI Insight ', vol: 5, pages: 135459-1-135459-15 (2020) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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. A monoclonal antibody developed as a single-molecule probe has revealed pathological aggregates of α-1-antitrypsin capture the WT variant. |
| Databáze: | OpenAIRE |
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