Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin.

JCI Insight
Mattia LaffranchiJames A Irving

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 implication...Continue Reading

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Citations

Dec 6, 2020·International Journal of Molecular Sciences·Urszula LechowiczJoanna Chorostowska-Wynimko
Apr 4, 2021·International Journal of Molecular Sciences·Francesco Callea, Valeer Desmet
Jun 3, 2021·International Journal of Molecular Sciences·Riccardo RonzoniAnnamaria Fra
Jul 3, 2021·International Journal of Molecular Sciences·Francesco CalleaEmanuele Bellacchio
Aug 19, 2021·Cellular and Molecular Life Sciences : CMLS·Emanuela D'AcuntoElena Miranda
Sep 17, 2021·Respiratory Research·Alexa NúñezCristina Esquinas

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Methods Mentioned

BETA
ELISA
chip
electrophoretic mobility shift assay
electron microscopy
electron
ion-exchange chromatography
size exclusion chromatography
x-ray diffraction

Software Mentioned

GraphPad
ImageJ
Prism5
PyMOL
EMAN2
XDS
PHENIX
PHASER
XIA2
COOT

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