The mechanism of Z α1-antitrypsin accumulation in the liver (original) (raw)

Nature volume 357, pages 605–607 (1992)Cite this article

Abstract

MOST northern Europeans have only the normal M form of the plasma protease inhibitor _α_1,-antitrypsin, but some 4% are heterozygotes for the Z deficiency variant1. For reasons that have not been well-understood, the Z mutation results in a blockage in the final stage of processing of antitrypsin in the liver2such that in the Z homozygote only 15% of the protein is secreted into the plasma. The 85% of the _α_1, -antitrypsin that is not secreted accumulates in the endoplasmic reticulum of the hepatocyte; much of it is degraded but the remainder aggregates to form insoluble intracellular inclusions. These inclusions are associated with hepatocellular damage, and 10% of newborn Z homozygotes develop liver disease which often leads to a fatal childhood cirrhosis. Here we demonstrate the molecular pathology underlying this accumulation and describe how the Z mutation in antitrypsin results in a unique molecular interaction between the reactive centre loop of one molecule and the gap in the A-sheet of another. This loop–sheet polymerization of Z antitrypsin occurs spontaneously at 37 °C and is completely blocked by the insertion of a specific peptide into the A-sheet of the antitrypsin molecule. Z antitrypsin polymerized in vitro has identical properties and ultra-structure to the inclusions isolated from hepatocytes of a Z homozygote. The concentration and temperature dependence of this loop–sheet polymerization has implications for the management of the liver disease of the newborn Z homozygote.

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Author notes

  1. John T. Finch: MRC Laboratory of Molecular Biology, MRC Centre, Hills Road, Cambridge CB2 2QH, UK

Authors and Affiliations

  1. Department of Haematology, University of Cambridge, and,
    David A. Lomas, Dyfed LI-Evans, John T. Finch & Robin W. Carrell

Authors

  1. David A. Lomas
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  2. Dyfed LI-Evans
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  3. John T. Finch
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  4. Robin W. Carrell
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Lomas, D., LI-Evans, D., Finch, J. et al. The mechanism of Z _α_1-antitrypsin accumulation in the liver.Nature 357, 605–607 (1992). https://doi.org/10.1038/357605a0

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