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Z alpha 1-antitrypsin accumulation in the liver.
03.05.2009
Nature. 1992 Jun 18;
D A Lomas, D L Evans, J T Finch, R W Carrell
Most northern Europeans have only the normal M form of the plasma protease inhibitor alpha 1-antitrypsin, but some 4% are heterozygotes for the Z deficiency variant. 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 liver such that in the Z homozygote only 15% of the protein is secreted into the plasma. The 85% of the alpha 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 degrees 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 ultrastructure 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.
Mesh-terms: Circular Dichroism; Homozygote; Human; Liver :: metabolism; Liver Diseases :: etiology; Macromolecular Systems; Mutation; Polymers; Protein Conformation; Support, Non-U.S. Gov't; alpha 1-Antitrypsin :: genetics; alpha 1-Antitrypsin :: metabolism; alpha 1-Antitrypsin Deficiency
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