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₁-Antitrypsin Inhibits the Activity of the Matriptase Catalytic Domain In Vitro

¹ Lund University, Department of Clinical Sciences, The Wallenberg Laboratory, Malmö University Hospital, Malmö, Sweden; ² Departments of Anesthesiology, ³ Physiology and Biophysics, ⁴ Environmental Health Sciences, ⁵ Center of Free Radical Biology, and ⁶ Center of Pulmonary Injury and Repair, University of Alabama at Birmingham, School of Medicine, Birmingham, Alabama

Correspondence and requests for reprints should be addressed to Sabina Janciauskiene, Ph.D., Dept. of Clinical Sciences, Wallenberg Laboratory, Malmö University Hospital, SE-20502 Malmö, Sweden. E-mail: sabina.janciauskiene{at}med.lu.se.

Matriptase is a type II transmembrane protease that is characterized by an N-terminal transmembrane and multiple extracellular domains, in addition to the conserved extracellular serine protease catalytic domain. The expression pattern of matriptase suggests that this protease may play broad roles in the biology of surface lining epithelial cells. In this study we report that ₁-antitrypsin (AAT), an endogenous inhibitor of serine proteases, inhibits the catalytic domain of human recombinant matriptase in vitro. Co-incubation of AAT with matriptase (at a molar ratio 1:2) resulted in the formation of heat stable complexes, clearly seen in sodium dodecyl sulfate electrophoresis and Western blots. AAT was found to be a slow, tight-binding inhibitor of the catalytic domain of matriptase with a second order reaction rate constant of 0.31 x 10³ M^–1s^–1. Notably, the oxidized form of AAT, which lacks serine protease inhibitor activity, failed to generate matriptase complexes and to inhibit matriptase activity. Since matriptase is involved in a number of physiologic processes, including activation of epithelial sodium channels, our findings offer considerable new insights into new regulatory function of AAT in vivo.

Key Words: serine proteases • ₁-antitrypsin • matriptase • complex formation • kinetics