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J. Biol. Chem., Vol. 283, Issue 5, 2478-2487, February 1, 2008

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Roles of Functional and Structural Domains of Hepatocyte Growth Factor Activator Inhibitor Type 1 in the Inhibition of Matriptase^*

Kenji Kojima¹, Satoshi Tsuzuki¹, Tohru Fushiki, and Kuniyo Inouye²

From the Laboratories of Enzyme Chemistry and Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound, Kunitz-type serine protease inhibitor. HAI-1 inhibits serine proteases that have potent pro-hepatocyte growth factor-converting activity, such as the membrane-type serine protease, matriptase. HAI-1 comprises an N-terminal domain, followed by an internal domain, first protease inhibitory domain (Kunitz domain I), low-density lipoprotein receptor A module (LDLRA) domain, and a second Kunitz domain (Kunitz domain II) in the extracellular region. Our aim was to assess the roles of these domains in the inhibition of matriptase. Soluble forms of recombinant rat HAI-1 mutants made up with various combinations of domains were produced, and their inhibitory activities toward the hydrolysis of a chromogenic substrate were analyzed using a soluble recombinant rat matriptase. Kunitz domain I exhibited inhibitory activity against matriptase, but Kunitz domain II did not. The N-terminal domain and Kunitz domain II decreased the association rate between Kunitz domain I and matriptase, whereas the internal domain increased this rate. The LDLRA domain suppressed the dissociation of the Kunitz domain I-matriptase complex. Surprisingly, an HAI-1 mutant lacking the N-terminal domain and Kunitz domain II showed an inhibitor constant of 1.6 pM, and the inhibitory activity was 400 times higher in this HAI-1 mutant than in the mutant with all domains. These findings, together with the known occurrence of an HAI-1 species lacking the N-terminal domain and Kunitz domain II in vivo, suggest that the domain structure of HAI-1 is organized in a way that allows HAI-1 to flexibly control matriptase activity.

Received for publication, November 5, 2007

^* This work was supported by Grants-in-aid for Scientific Research 14658203 and 17380065 (to K. I.) from the Japan Society for the Promotion of Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Laboratory of Enzyme Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. Tel.: 81-75-753-6266; Fax: 81-75-753-6265; E-mail: inouye{at}kais.kyoto-u.ac.jp.

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				K. Kojima, S. Tsuzuki, T. Fushiki, and K. Inouye Role of the Stem Domain of Matriptase in the Interaction with its Physiological Inhibitor, Hepatocyte Growth Factor Activator Inhibitor Type I J. Biochem., June 1, 2009; 145(6): 783 - 790. [Abstract] [Full Text] [PDF]