Abstract
Alpha1-antitrypsin deficiency results from point mutations that distort the structure of the protein to allow a unique protein–protein interaction that we have termed loop-sheet polymerization. Polymers of Zα1 -antitrypsin accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z α1-antitrypsin homozygote to emphysema. This polymerization process also occurs in variants of other members of the serine proteinase inhibitor (serpin) superfamily, antithrombin, C1-inhibitor and α1-antichymotrypsin in association with thrombosis, angio-oedema and chronic obstructive pulmonary disease respectively, and we have recently shown that it underlies a novel inclusion body dementia. Understanding this mechanism of polymerization allows rational drug design to block the protein–protein linkage and so ameliorate the associated disease.
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