Surface activation of pro-cathepsin L

Mason, Robert W.; Massey, Steven D.

doi:10.1016/0006-291x(92)90268-p

Cited by 96 publications

(67 citation statements)

References 17 publications

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“…As we have evidenced, polyanionic compounds not only are able to markedly enhance the yields and rates of pro-TPP activation, but what may be especially important, they also are extending pro-TPP I activation toward less acidic pH, bringing the feasibility of pro-TPP I autoactivation within the physiological pH range of lysosomes. Similar stimulatory effect of GAGs also was reported for two lysosomal cysteine proteases, pro-cathepsins B and L (34,35,49). Interestingly, congopain, the major cysteine protease from Trypanosoma congolense, was activated in the presence of DS, even at a basic pH as high as 8.0 (33).…”

Section: Discussionsupporting

confidence: 79%

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Glycosaminoglycans Modulate Activation, Activity, and Stability of Tripeptidyl-peptidase I in Vitro and in Vivo

Golabek

Walus

Wisniewski

et al. 2005

Journal of Biological Chemistry

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Tripeptidyl-peptidase I (TPP I, CLN2 protein) is a lysosomal exopeptidase that sequentially removes tripeptides from the N termini of polypeptides and shows a minor endoprotease activity. Mutations in TPP I lead to classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disease. TPP I proenzyme is converted in lysosomes into a mature enzyme with the assistance of another protease and is able to autoactivate in acidic pH in vitro via a unimolecular mechanism. Because autoactivation in vitro at the pH values reported for lysosomes generated inactive enzyme, we intended to determine whether physiologically relevant factors can modify this process to also make it plausible in vivo. Here, we report that high ionic strength and glycosaminoglycans (GAGs) increase yields (ionic strength) or yields and rates (GAGs) of activation, enhance degradation of liberated TPP I prosegment fragments, and switch effective autoactivation of TPP I proenzyme toward less acidic pH values (up to pH 6.0). Although ionic strength and GAGs also inhibited TPP I activity in vitro and in living cells, the degree of inhibition (from 20 to 60%) appears to be of rather limited functional significance. Importantly, binding to GAGs improved thermal stability of TPP I and protected the enzyme against alkaline pH-induced denaturation in vitro (t1 ⁄2 of mature enzyme at pH 7.4 increased by ϳ8-fold in the presence of heparin) and in vivo (ϳ2-fold higher loss of TPP I in cells deficient in GAGs than in control cells after bafilomycin A1 treatment). These findings elucidate a potent physiologically relevant mechanism of TPP I regulation by GAGs and suggest that generation of the active enzyme via autoactivation can be accomplished not only in vitro but in vivo as well.

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Section: Discussionsupporting

confidence: 79%

“…The Effect of GAGs on Pro-TPP I Maturation in Vitro-It was demonstrated that negatively charged compounds, such as dextran sulfate (DS), are able to accelerate the processing of several lysosomal enzymes including cathepsins B and L (34,35).…”

Section: The Effect Of Ionic Strength On Autoactivation Of Pro-tpp I-itmentioning

confidence: 99%

Glycosaminoglycans Modulate Activation, Activity, and Stability of Tripeptidyl-peptidase I in Vitro and in Vivo

Golabek

Walus

Wisniewski

et al. 2005

Journal of Biological Chemistry

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“…Mason and Massey showed [18] that procathepsin L was auto-activated by contact with negatively charged materials such as dextran sulfate in acidic condition at pH 5.5. Ishidoh and Kominami also reported [19] that procathepsin L purified from v-Ha-ras transformed NIH3T3 cell conditioned medium was autocatalytically converted to the mature enzyme by incubation for 30 min at 37°C in sodium acetate buffer, pH 5.5, containing dextran sulfate and dithiothreitol.…”

Section: Participation Of Cysteine Proteinase(s) In Post-secretional mentioning

confidence: 99%

Secretion and processing mechanisms of procathepsin L in bone resorption

Kakegawa¹,

Tagami²,

Ohba³

et al. 1995

FEBS Letters

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Secretion of procathepsin L into the culture medium from a bone cell mixture was markedly enhanced by addition of parathyroid hormone (PTH), 1 a,25-(OH)2D 3 or tumor necrosis factor a (TNFa). These stimulators of secretion of procathepsin L enhanced bone pit formation, which was inhibited by E-64, but not by CA-074, a specific inhibitor of cathepsin B. Procathepsin L may thus participate in the process of bone collagenolysis during bone resorption. Procathepsin L partially purified from rat long bones under cold conditions was rapidly converted to the mature form under acidic conditions at room temperature. This conversion was inhibited by E-64, suggesting that the procathepsin L secreted into lacunae is catalytically converted to the mature enzyme by cysteine proteinase(s).In the present study, designed to clarify the mechanism and regulation of both the secretion of procathepsin L and its processing in lacunae, we examined the secretion of procathepsin L induced by 10~,25-(OH)2D 3, TNFc~ or by PTH, and also the effects of the cysteine proteinase inhibitors, E-64 and CA-074, on the pit formation induced by these effectors. Furthermore, to clarify the participation of cysteine proteinase(s) in processing from the precursor to the active form, the inhibitory effect of E-64 on the processing of procathepsin L partially purified from rat long bones was also examined. Experimental

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“…The proregion of cathepsin L is compulsory for its correct folding either in vivo (23) or in vitro (24). Activation of cathepsin L occurs autocatalytically below pH 4 (11, 25), and also at higher pH (around pH 5.5) in the presence of anionic oligosaccharides such as dextran sulfate or heparin (26,27). This mode of activation is very similar to that of other cysteine proteases of the papain family (28, 29).…”

mentioning

confidence: 94%

pH-induced Conformational Transitions of the Propeptide of Human Cathepsin L

Jerala

Žerovnik

Kidrič

et al. 1998

Journal of Biological Chemistry

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Synthesis of proteases as inactive zymogens is a very important mechanism for the regulation of their activity. For lysosomal proteases proteolytic cleavage of the propeptide is triggered by the acidic pH. By using fluorescence, circular dichroism, and NMR spectroscopy, we show that upon decreasing the pH from 6.5 to 3 the propeptide of cathepsin L loses most of the tertiary structure, but almost none of the secondary structure is lost. Another partially structured intermediate, prone to aggregation, was identified between pH 6.5 and 4. The conformation, populated below pH 4, where the activation of cathepsin L occurs, is not completely unfolded and has the properties of molten globule, including characteristic binding of the 1-anilinonaphthalene-8-sulfonic acid. This pH unfolding of the propeptide parallels a decrease of its affinity for cathepsin L and suggests the mechanism for the acidic zymogen activation. Addition of anionic polysaccharides that activate cathepsin L already at pH 5.5 unfolds the tertiary structure of the propeptide at this pH. Propeptide of human cathepsin L which is able to fold independently represents an evolutionary intermediate in the emergence of novel inhibitors originating from the enzyme proregions.All lysosomal and most other proteases are synthesized in the form of inactive precursors (1, 2). Propeptides are generally located N-terminal to the mature enzyme, and activation of the enzyme is accomplished by cis-or trans-cleavage of the propeptide. Propeptides vary from a few (e.g. trypsin) to more than 200 residues (e.g. cathepsin C). Longer propeptides are generally strong and specific inhibitors of their mature enzymes (3-7). In most cases propeptides are also indispensable for correct folding of the enzymes (8). In some enzymes folding of the mature form is extremely slow, and the propeptide assists in overcoming the kinetic barrier (9), which may also be overcome by physicochemical factors such as high ionic strength in subtilisin, for example (10). Proenzymes are quite often more stable than mature enzymes (11, 12) and can represent a pool of latent enzyme until the activation occurs in the proper conditions. Propeptides are also involved in targeting to specific organelles (13, 14); they can affect posttranslational modification such as glycosylation (15) and mediate interactions with other molecules (16,17). Propeptides can be cleaved either by other proteases or by intra-or intermolecular autocatalysis. pH change is one of the most common environmental parameters responsible for triggering the activation of proteases, occurring in cysteine, aspartic acid, and metalloproteases (1,18,19). Low pH is thought either to increase the susceptibility of the propeptide as a substrate due to the protonation of groups close to the cleavage site or to cause a conformational change in the propeptide or enzyme.Cathepsin L is one of the most active cysteine proteases and accounts for most of the lysosomal cysteine protease activity (20). It has been implicated in a range of processes incl...

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Surface activation of pro-cathepsin L

Cited by 96 publications

References 17 publications

Glycosaminoglycans Modulate Activation, Activity, and Stability of Tripeptidyl-peptidase I in Vitro and in Vivo

Glycosaminoglycans Modulate Activation, Activity, and Stability of Tripeptidyl-peptidase I in Vitro and in Vivo

Secretion and processing mechanisms of procathepsin L in bone resorption

pH-induced Conformational Transitions of the Propeptide of Human Cathepsin L

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