Autocatalytic processing of procathepsin B is triggered by proenzyme activity. FEBS J. 276, 660-668

Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, Ljubljana, Slovenia.
FEBS Journal (Impact Factor: 4). 03/2009; 276(3):660-8. DOI: 10.1111/j.1742-4658.2008.06815.x
Source: PubMed


Cathepsin B (EC and other cysteine proteases are synthesized as zymogens, which are processed to their mature forms autocatalytically or by other proteases. Autocatalytic processing was suggested to be a bimolecular process, whereas initiation of the processing has not yet been clarified. Procathepsin B was shown by zymography to hydrolyze the synthetic substrate 7-N-benzyloxycarbonyl-L-arginyl-L-arginylamide-4-methylcoumarin (Z-Arg-Arg-NH-MEC), suggesting that procathepsin B is catalytically active. The activity-based probe DCG-04, which is an E-64-type inhibitor, was found to label both mature cathepsin B and its zymogen, confirming the zymography data. Mutation analyses in the linker region between the propeptide and the mature part revealed that autocatalytic processing of procathepsin B is largely unaffected by mutations in this region, including mutations to prolines. On the basis of these results, a model for autocatalytic activation of cysteine cathepsins is proposed, involving propeptide dissociation from the active-site cleft as the first step during zymogen activation. This unimolecular conformational change is followed by a bimolecular proteolytic removal of the propeptide, which can be accomplished in one or more steps. Such activation, which can be also facilitated by glycosaminoglycans or by binding to negatively charged surfaces, may have important physiological consequences because cathepsin zymogens were often found secreted in various pathological states.

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    • "Exceptionally, CatS, remains catalytically active under neutral pH and remains stable outside the lysosome. Like CatB and CatL, CatS undergoes autoactivation (Pungercar et al., 2009). Interestingly , glycosaminoglycans promote the autocatalytic processing of cathepsins to their mature forms (Caglic et al., 2007). "
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    ABSTRACT: Dyslipemia has a direct impact on cardiac remodeling by altering extracellular matrix (ECM) components. One of the main ECM components is elastin, a proteic three-dimensional network that can be efficiently degraded by cysteine proteases or cathepsins. Dyslipemic status in insulin resistance and combined hyperlipoproteinemia diseases include raised levels of very low density lipoproteins (VLDL), triglyceride (TG)-cholesteryl ester (CE)-rich lipoproteins. Enhanced VLDL concentration promotes cardiomyocyte intracellular cholesteryl ester (CE) accumulation in a LRP1-dependent manner. The aim of this work was to analyze the effect of cardiomyocyte intracellular CE accumulation on tropoelastin (TE) characteristics and to investigate the role of LRP1 and Cathepsin S (CatS) on these effects. Molecular studies showed that LRP1 deficiency impared CE selective uptake and accumulation from TG-CE- rich lipoproteins (VLDL+IDL) and CE-rich lipoproteins (aggregated LDL, agLDL). Biochemical and confocal microscopic studies showed that LRP1-mediated intracellular CE accumulation increased CatS mature protein levels and induced an altered intracellular TE globule structure. Biophysical studies evidenced that LRP1-mediated intracellular CE accumulation caused a significant drop of Tg2 glass transition temperature of cardiomyocyte secreted TE. Moreover, CatS deficiency prevented the alterations in TE intracellular globule structure and on TE glass transition temperature. These results demonstrate that LRP1-mediated cardiomyocyte intracellular CE accumulation alters the structural and physical characteristics of secreted TE through an increase in CatS mature protein levels. Therefore, the modulation of LRP1-mediated intracellular CE accumulation in cardiomyocytes could impact pathological ventricular remodeling associated with insulin-resistance and combined hyperlipoproteinemia, pathologies characterized by enhanced concentrations of TG-CE-rich lipoproteins.
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    • "Their activation can be autocatalytic or catalyzed by other proteases [14] [38]. However, even during autocatalytic activation, activation is always in trans, i.e. one cathepsin or procathepsin molecule activating another procathepsin molecule [39]. In contrast to endopeptidases , exopeptidases cathepsins C and X cannot be autocatalytically activated but require an endopeptidase such as cathepsin L or S for their activation [40] [41]. "
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    ABSTRACT: Cysteine cathepsins are normally found in the lysosomes where they are involved in intracellular protein turnover. Their ability to degrade the components of the extracellular matrix in vitro was first reported more than 25 years ago. However, cathepsins were for a long time not considered to be among the major players in ECM degradation in vivo. During the last decade it has, however, become evident that abundant secretion of cysteine cathepsins into extracellular milieu is accompanying numerous physiological and disease conditions, enabling the cathepsins to degrade extracellular proteins. In this review we will focus on cysteine cathepsins and their extracellular functions linked with ECM degradation, including regulation of their activity, which is often enhanced by acidification of the extracellular microenvironment, such as found in the bone resorption lacunae or tumor microenvironment. We will further discuss the ECM substrates of cathepsins with a focus on collagen and elastin, including the importance of that for pathologies. Finally, we will overview the current status of cathepsin inhibitors in clinical development for treatment of ECM-linked diseases, in particular osteoporosis. Due to their major role in ECM remodelling cysteine cathepsins have emerged as an important group of therapeutic targets for a number of ECM-related diseases, including, osteoporosis, cancer and cardiovascular diseases. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties..
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    • "Procathepsin B was a pro-form of active mature form of cathepsin B (8,9) and could be suggested as a new tumour biomarker in ovarian cancer. "
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