The Occluding Loop of Cathepsin B Prevents Its Effective Inhibition by Human Kininogens

Naudin, Clément; Lecaille, Fabien; Chowdhury, Subrata; Krupa, Joanne C.; Purisima, Enrico O.; Mort, John S.; Lalmanach, Gilles

doi:10.1016/j.jmb.2010.06.006

Cited by 18 publications

(9 citation statements)

References 81 publications

(88 reference statements)

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“…Similar degradation of kininogens have been found in other inflammatory body fluids, like synovial and amniotic fluids, and blood plasma (for review: [30]). The lack of undamaged kininogens together with the presence of kininogen fragments ( circa 20–40 kDa) correlates with the recent demonstration that the inability of kininogens to inhibit cathepsin B (in contrast to cathepsins L and S) is associated with their extensive cleavage by cathepsin B [31]. We have also shown that Biot-LVG-CHN 2 , a cystatin C-derived activity-based probe, binds to sputum cysteine cathepsins.…”

Section: Resultssupporting

confidence: 79%

“…Our data also confirmed that significant amounts of cathepsins may escape regulation by their endogenous inhibitors. This, together with the recent demonstration that the poor inactivation of cathepsin B (unlike the tight-binding inhibition of cathepsins L and S) by kininogens is associated with their extensive cleavage by cathepsin B [31], indicates that cathepsin B is a major protease involved in this process in CF sputum. This is also true for several other inflammatory disorders (for review: [30]).…”

Section: Resultsmentioning

confidence: 87%

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Human Cysteine Cathepsins Are Not Reliable Markers of Infection by Pseudomonas aeruginosa in Cystic Fibrosis

et al. 2011

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Cysteine cathepsins have emerged as new players in inflammatory lung disorders. Their activities are dramatically increased in the sputum of cystic fibrosis (CF) patients, suggesting that they are involved in the pathophysiology of CF. We have characterized the cathepsins in CF expectorations and evaluated their use as markers of colonization by Pseudomonas aeruginosa. The concentrations of active cathepsins B, H, K, L and S were the same in P. aeruginosa-positive (19 Ps+) and P. aeruginosa-negative (6 Ps−) samples, unlike those of human neutrophil elastase. Also the cathepsin inhibitory potential and the cathepsins/cathepsin inhibitors imbalance remained unchanged and similar (∼2-fold) in the Ps+ and Ps− groups (p<0.001), which correlated with the breakdown of their circulating cystatin-like inhibitors (kininogens). Procathepsins, which may be activated autocatalytically, are a potential proteolytic reservoir. Immunoblotting and active-site labeling identified the double-chain cathepsin B, the major cathepsin in CF sputum, as the main molecular form in both Ps+ and Ps− samples, despite the possible release of the ∼31 kDa single-chain form from procathepsin B by sputum elastase. Thus, the hydrolytic activity of cysteine cathepsins was not correlated with bacterial colonization, indicating that cathepsins, unlike human neutrophil elastase, are not suitable markers of P. aeruginosa infection.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 87%

Human Cysteine Cathepsins Are Not Reliable Markers of Infection by Pseudomonas aeruginosa in Cystic Fibrosis

et al. 2011

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“…Lesser inhibition of cathepsin B is generally explained by the presence of an occluding loop in this protease which covers the active site and causes slow association of the inhibitor [29][30][31][32]. Likewise, the here characterized F. gigantica Stefin-2 can be classified as a type 1 cystatin based on its amino acid sequence (Fig.…”

Section: Discussionmentioning

confidence: 90%

Efficient inhibition of cathepsin B by a secreted type 1 cystatin of Fasciola gigantica

Siricoon

Grams

2012

Molecular and Biochemical Parasitology

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“…On the other hand, cathepsin B is poorly inhibited by kininogens due to the residues His110-His111 positioned within its occluding loop. The His110Ala cathepsin B mutant, unlike its His111Ala mutant, does not hydrolyze kininogens but forms a tight-binding complex [257].…”

Section: Mechanism Of Inhibition Of Cysteine Cathepsinsmentioning

confidence: 98%

Cysteine cathepsins: From structure, function and regulation to new frontiers

Türk

Stoka

Vasiljeva

et al. 2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

1,086

1,054

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It is more than 50 years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these are the cysteine cathepsins, members of the family of papain-like cysteine proteases. They have unique reactive-site properties and an uneven tissue-specific expression pattern. In living organisms their activity is a delicate balance of expression, targeting, zymogen activation, inhibition by protein inhibitors and degradation. The specificity of their substrate binding sites, small-molecule inhibitor repertoire and crystal structures are providing new tools for research and development. Their unique reactive-site properties have made it possible to confine the targets simply by the use of appropriate reactive groups. The epoxysuccinyls still dominate the field, but now nitriles seem to be the most appropriate "warhead". The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments. Besides being involved in protein turnover, they build an important part of the endosomal antigen presentation. Together with the growing number of non-endosomal roles of cysteine cathepsins is growing also the knowledge of their involvement in diseases such as cancer and rheumatoid arthritis, among others. Finally, cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes. The current challenge is to identify their endogenous substrates, in order to gain an insight into the mechanisms of substrate degradation and processing. In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

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The Occluding Loop of Cathepsin B Prevents Its Effective Inhibition by Human Kininogens

Abstract: The occluding loop of Cathepsin B prevents its effective inhibition by human kininogens Naudin, C.; Lecaille, F.; Chowdhury, S.; Krupa, J. C.; Purisima, E.; Mort, J.S.; Lalmanach, G.Contact us / Contactez nous: nparc.cisti@nrc-cnrc.gc.ca.

Cited by 18 publications

References 81 publications

Human Cysteine Cathepsins Are Not Reliable Markers of Infection by Pseudomonas aeruginosa in Cystic Fibrosis

Human Cysteine Cathepsins Are Not Reliable Markers of Infection by Pseudomonas aeruginosa in Cystic Fibrosis

Efficient inhibition of cathepsin B by a secreted type 1 cystatin of Fasciola gigantica

Cysteine cathepsins: From structure, function and regulation to new frontiers

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