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Protein Engineering vol. 1 no. 1 pp. 29-35, 1986
© 1986 Oxford University Press

RESEARCH-ARTICLE

Altered specificities of genetically engineered {alpha}1 antitrypsin variants

S. Jallat, D. Carvallo1, L.H. Tessier, D. Roecklin1, C. Roitsch1, F. Ogushi2, R.G. Crystal2 and M. Courtney3

Department of Molecular Biology, Transgene S A, II rue de Molsheim 67000 Strasbourg, France 1Department of Protein Chemistry, Transgene S A, II rue de Molsheim 67000 Strasbourg, France 2National Heart, Lung and Blood Institute. National Institutes of Health Bethesda, MD 20205, USA

3To whom reprint requests should be sent

Seven active site variants of human {alpha}1-antitrypsin ({alpha}1AT) were produced in Escherichia coli following site-specific mutagenesis of the {alpha}1AT complementary DNA. {alpha}1AT (Ala 358), {alpha}1AT (Ile358 and {alpha}1AT (Val358), were efficient inhibitors of both neutrophil and pancreatic elastases, but not of cathepsin G. {alpha}1AT (Ala358, Val358) and {alpha}1AT (Phe358 specifically inhibited pancreatic elastase and cathepsin G respectively. The most potent inhibitor of neutrophil elastase was {alpha}1AT (Leu358), which also proved to be effective against cathepsin G. The {alpha}1AT (Arg358) variant inactivated thrombin with kinetics similar to antithrombin III in the presence of heparin. Electrophoretic analysis showed that SDS-stable high mol. wt complexes were formed between the mutant inhibitors and the cognate proteases in each case. These data indicate that effective inhibition occurs when the {alpha}1AT P1 residue (position 358) corresponds to the primary specificity of the target protease. Moreover, alteration of the P3 residue (position 356) can further modify the reactivity of the inhibitor. Two of the variants have therapeutic potential: {alpha}1AT (Leu358 may be more useful than plasma {alpha}1AT in the treatment of destructive lung disorders and {alpha}1 (Arg358 could be effective in the control of thrombosis.

Keywords: {alpha}1-antitrypsin/neutrophil proteases/pulmonary emphysema/thrombin/thrombosis

Received June 18, 1986;
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