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Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin

DOI: 10.1172/jci.insight.135459 DOI Help
Data DOI: 10.2210/pdb6I1O/pdb Data DOI Help
PMID: 32699193 PMID Help

Authors: Mattia Laffranchi (University of Brescia; University College London) , Emma L. K. Elliston (University College London) , Elena Miranda (Sapienza University of Rome) , Juan Perez (Universidad de Malaga) , Riccardo Ronzoni (University College London) , Alistair M. Jagger (University College London) , Nina Heyer-Chauhan (University College London) , Mark L. Brantly (University of Florida) , Annamaria Fra (University of Brescia) , David A. Lomas (University College London) , James A. Irving (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Jci Insight , VOL 5 , PAGES e135459

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 17201

Open Access Open Access

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.

Journal Keywords: Diagnostics; Genetic diseases; Genetics; Hepatology; Structural biology

Diamond Keywords: Liver Disease

Subject Areas: Medicine, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF beamline ID29

Added On: 24/07/2020 00:58

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Genetics Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)