α1-Antitrypsin functions as a ‘mousetrap’ to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant (Glu342 → Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and β-sheet A of another. These loop-sheet polymers 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. Loop-sheet polymerization is now recognized to underlie deficiency variants of other members of the serine proteinase inhibitor (serpin) superfamily, i.e. antithrombin, C1 esterase inhibitor and α1-anti-chymotrypsin, which are associated with thrombosis, angio-oedema and emphysema respectively. Moreover, we have shown recently that the same process in a neuron-specific protein, neuroserpin, underlies a novel inclusion-body dementia, known as familial encephalopathy with neuroserpin inclusion bodies. Our understanding of the structural basis of polymerization has allowed the development of strategies to prevent the aberrant protein-protein interaction in vitro. This must now be achieved in vivo if we are to treat the associated clinical syndromes.
Conference Article| April 01 2002
Hypersensitive mousetraps, α1-antitrypsin deficiency and dementia
D. A. Lomas;
D. A. Lomas 1
1Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, U.K.
1To whom correspondence should be addressed (e-mail firstname.lastname@example.org).
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D. A. Lomas, A. Lourbakos, S.-A. Cumming, D. Belorgey; Hypersensitive mousetraps, α1-antitrypsin deficiency and dementia. Biochem Soc Trans 1 April 2002; 30 (2): 89–92. doi: https://doi.org/10.1042/bst0300089
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