The Inhibition of Cathepsin S by its Propeptide — Specificity and Mechanism of Action

Maubach, Gunter; Schilling, Klaus; Rommerskirch, Winfried; Wenz, Ingrid; Schultz, Joachim E.; Weber, Ekkehard; Wiederanders, Bernd

doi:10.1111/j.1432-1033.1997.00745.x

Cited by 74 publications

(74 citation statements)

References 25 publications

(16 reference statements)

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“…Cathepsins-Cathepsin B was purified from rat liver (13), cathepsin H from Epstein-Barr virus transformed human B-lymphocytes (14), and cathepsin L from the culture medium of non-small cell lung cancer cell line EPLC 32 M1 (15). All cathepsins were purified to homogeneity, and the concentration of the cathepsins was determined by titration with E64 (16).…”

Section: Methodsmentioning

confidence: 99%

Defective Oligomerization of Arylsulfatase A as a Cause of Its Instability in Lysosomes and Metachromatic Leukodystrophy

Bülow

Schmidt

Dierks

et al. 2002

Journal of Biological Chemistry

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In one of the most common mutations causing metachromatic leukodystrophy, the P426L-allele of arylsulfatase A (ASA), the deficiency of ASA results from its instability in lysosomes. Inhibition of lysosomal cysteine proteinases protects the P426L-ASA and restores the sulfatide catabolism in fibroblasts of the patients. P426L-ASA, but not wild type ASA, was cleaved by purified cathepsin L at threonine 421 yielding 54-and 9-kDa fragments. X-ray crystallography at 2.5-Å resolution showed that cleavage is not due to a difference in the protein fold that would expose the peptide bond following threonine 421 to proteases. Octamerization, which depends on protonation of Glu-424, was impaired for P426L-ASA. The mutation lowers the pH for the octamer/ dimer equilibrium by 0.6 pH units from pH 5.8 to 5. Arylsulfatase A (ASA) 1 is a lysosomal enzyme that is synthesized as a 52-kDa polypeptide. In the endoplasmic reticulum ASA receives three N-linked oligosaccharides, undergoes con-

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Section: Methodsmentioning

confidence: 99%

Defective Oligomerization of Arylsulfatase A as a Cause of Its Instability in Lysosomes and Metachromatic Leukodystrophy

Bülow

Schmidt

Dierks

et al. 2002

Journal of Biological Chemistry

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“…21 For the cathepsin L propeptide, lack of inhibition has been associated with partial unfolding of the propeptide and formation of a molten globule state under acidic conditions. 25 Moreover, under these conditions, it has been demonstrated that the cathepsin S propeptide is slowly degraded by mature cathepsin L. 21 To date, the interaction between mature Der p 1 and its propeptide has not been investigated due to the difficulty of obtaining correctly matured recombinant Der p 1 (rDer p 1). In order to characterize this interaction, we studied the activation steps involved in the zymogen maturation mechanism.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…[21][22][23][24] Some cathepsin propeptides have been shown to display a strong inhibition capacity at neutral pH, with values of the dissociation constant K D ranging from 0.12 nM for cathepsins L and B to 7.6 nM for cathepsins S and K. Interactions between the propeptides and the proteases are pH dependent: At neutral pH, slow binding interactions occur, whereas at acidic pH, weak or no interactions are observed. 21 For the cathepsin L propeptide, lack of inhibition has been associated with partial unfolding of the propeptide and formation of a molten globule state under acidic conditions. 25 Moreover, under these conditions, it has been demonstrated that the cathepsin S propeptide is slowly degraded by mature cathepsin L. 21 To date, the interaction between mature Der p 1 and its propeptide has not been investigated due to the difficulty of obtaining correctly matured recombinant Der p 1 (rDer p 1).…”

Section: Introductionmentioning

confidence: 99%

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Relationship between Propeptide pH Unfolding and Inhibitory Ability during ProDer p 1 Activation Mechanism

Chevigné

Barumandzadeh

Groslambert

et al. 2007

Journal of Molecular Biology

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The major allergen Der p 1 of the house dust mite Dermatophagoides pteronyssinus is a papain-like cysteine protease (CA1) produced as an inactive precursor and associated with allergic diseases. The propeptide of Der p 1 exhibits a specific fold that makes it unique in the CA1 propeptide family. In this study, we investigated the activation steps involved in the maturation of the recombinant protease Der p 1 expressed in Pichia pastoris and the interaction of the full-length and truncated soluble propeptides with their parent enzyme in terms of activity inhibition and BIAcore interaction analysis. According to our results, the activation of protease Der p 1 is a multistep mechanism that is characterized by at least two intermediates. The propeptide strongly inhibits unglycosylated and glycosylated recombinant Der p 1 (K D = 7 nM) at neutral pH. This inhibition is pH dependent. It decreases from pH 7 to pH 4 and can be related to conformational changes of the propeptide characterized by an increase of its flexibility and formation of a molten globule state. Our results indicate that activation of the zymogen at pH 4 is a compromise between activity preservation and propeptide unfolding.

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“…The NH 2 -terminal propeptide domain of the cathepsin L -like proteases is an inhibitor of the active enzyme in its latent form, which is then removed on its activation (7,8). Using purified proteases in peptidolytic assays, the ability of the propeptide to act as reversible inhibitors of their cognate protease has been shown (9,10).…”

Section: Introductionmentioning

confidence: 99%

Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment

Burden¹,

Snoddy

Buick

et al. 2008

Molecular Cancer Therapeutics

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Human cathepsin L along with cathepsin S, K, and V are collectively known as cathepsin L -like proteases due to their high homology. The overexpression and aberrant activity of each of these proteases has been implicated in tumorigenesis. These proteases contain propeptide domains that can potently inhibit both their cognate protease and other proteases within the cathepsin L -like subfamily. In this investigation, we have produced the cathepsin S propeptide recombinantly and have shown that it is a potent inhibitor of the peptidolytic, elastinolytic, and gelatinolytic activities of the cathepsin L -like proteases. In addition, we show that this peptide is capable of significantly attenuating tumor cell invasion in a panel of human cancer cell lines. Furthermore, fusion of an IgG Fc-domain to the COOH terminus of the propeptide resulted in a chimeric protein with significantly enhanced ability to block tumor cell invasion. This Fc fusion protein exhibited enhanced stability in cell-based assays in comparison with the unmodified propeptide species. This approach for the combined inhibition of the cathepsin L -like proteases may prove useful for the further study in cancer and other conditions where their aberrant activity has been implicated. Furthermore, this strategy for simultaneous inhibition of multiple cysteine cathepsins may represent the basis for novel therapeutics to attenuate tumorigenesis. [Mol Cancer Ther 2008;7(3):538 -47]

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The Inhibition of Cathepsin S by its Propeptide — Specificity and Mechanism of Action

Cited by 74 publications

References 25 publications

Defective Oligomerization of Arylsulfatase A as a Cause of Its Instability in Lysosomes and Metachromatic Leukodystrophy

Defective Oligomerization of Arylsulfatase A as a Cause of Its Instability in Lysosomes and Metachromatic Leukodystrophy

Relationship between Propeptide pH Unfolding and Inhibitory Ability during ProDer p 1 Activation Mechanism

Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L–like proteases in tumor microenvironment

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