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J. Biol. Chem., Vol. 282, Issue 11, 7893-7902, March 16, 2007

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Interaction between Human Cathepsins K, L, and S and Elastins

MECHANISM OF ELASTINOLYSIS AND INHIBITION BY MACROMOLECULAR INHIBITORS^*

Marko Novinec, Robert N. Grass, Wendelin J. Stark, Vito Turk, Antonio Baici^¶, and Brigita Lenari^||1

From the Department of Biochemistry and Molecular Biology, Joef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia, Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland, the ^¶Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland, and the ^||Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Jamova 39, SI-1000 Ljubljana, Slovenia

Proteolytic degradation of elastic fibers is associated with a broad spectrum of pathological conditions such as atherosclerosis and pulmonary emphysema. We have studied the interaction between elastins and human cysteine cathepsins K, L, and S, which are known to participate in elastinolytic activity in vivo. The enzymes showed distinctive preferences in degrading elastins from bovine neck ligament, aorta, and lung. Different susceptibility of these elastins to proteolysis was attributed to morphological differences observed by scanning electron microscopy. Kinetics of cathepsin binding to the insoluble substrate showed that the process occurs in two steps. The enzyme is initially adsorbed on the elastin surface in a nonproductive manner and then rearranges to form a catalytically competent complex. In contrast, soluble elastin is bound directly in a catalytically productive manner. Studies of enzyme partitioning between the phases showed that cathepsin K favors adsorption on elastin; cathepsin L prefers the aqueous environment, and cathepsin S is equally distributed among both phases. Our results suggest that elastinolysis by cysteine cathepsins proceeds in cycles of enzyme adsorption, binding of a susceptible peptide moiety, hydrolysis, and desorption. Alternatively, the enzyme may also form a new catalytic complex without prior desorption and re-adsorption. In both cases the active center of the enzymes remains at least partly accessible to inhibitors. Elastinolytic activity was readily abolished by cystatins, indicating that, unlike enzymes such as leukocyte elastase, pathological elastinolytic cysteine cathepsins might represent less problematic drug targets. In contrast, thyropins were relatively inefficient in preventing elastinolysis by cysteine cathepsins.

Received for publication, October 30, 2006 , and in revised form, December 15, 2006.

^* This work was supported by the Slovenian Research Agency Research Program P1-0140 and by Swiss National Science Foundation Grant 32-102108/1. 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 To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Jamova 39, SI-1000 Ljubljana, Slovenia. Tel.: 386-1-4773623; Fax: 386-1-4773984; E-mail: brigita.lenarcic{at}fkkt.uni-lj.si.

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