Laffranchi, M;
Elliston, EL;
Miranda, E;
Perez, J;
Ronzoni, R;
Jagger, AM;
Heyer-Chauhan, N;
... Irving, JA; + view all
(2020)
Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin.
JCI Insight
, 5
(14)
, Article e135459. 10.1172/jci.insight.135459.
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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.
| Type: | Article |
|---|---|
| Title: | Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/jci.insight.135459 |
| Publisher version: | http://dx.doi.org/10.1172/jci.insight.135459 |
| Language: | English |
| Additional information: | JCI Insight is an open access journal in which all content is freely available without charge to the user or their institution. Articles accepted beginning July 1, 2020, are published via the Creative Commons Attribution License (CC BY 4.0). Users of articles published under this license are allowed to read, download, copy, distribute, print, search, and link to the full texts of the articles, and use them for any other lawful purpose, without asking prior permission from the publisher or the author. |
| Keywords: | Diagnostics, Genetic diseases, Genetics, Hepatology, Structural biology |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine UCL > Provost and Vice Provost Offices > VP: Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10106609 |
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