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Article Dans Une Revue Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics Année : 2020

Rat cathepsin K: Enzymatic specificity and regulation of its collagenolytic activity

Résumé

Human cathepsin K (hCatK), which is highly expressed in osteoclasts, has the noteworthy ability to cleave type I and II collagens in their helical domain. Its collagenase potency depends strictly on the formation of an oligomeric complex with chondroitin 4-sulfate (C4-S). Accordingly, hCatK is a pivotal protease involved in bone resorption and is an attractive target for the treatment of osteoporosis. As rat is a common animal model for the evaluation of hCatK inhibitors, we conducted a comparative analysis of rat CatK (rCatK) and hCatK, which share a high degree of identity (88%) and similarity (93%). The pH activity profile of both enzymes displayed a similar bell-shaped curve (optimal pH: 6.4). Presence of Ser134 and Val160 in the S2 pocket of rCatK instead of Ala and Leu residues, respectively, in hCatK, led to a weaker peptidase activity, as observed for mouse CatK. Also, regardless of the presence of C4-S, rCatK cleaved in the nonhelical telopeptide regions of both type I (tail) and type II (articular joint) rat collagens. Structure-based computational analyses (electrostatic potential, molecular docking, molecular dynamics, free energy calculations) sustained that the C4-S mediated collagenolytic activity of rCatK obeys distinct molecular interactions from those of hCatK. Additionally, T-kininogen (a.k.a. thiostatin), a unique rat serum acute phase molecule, acted as a tight-binding inhibitor of hCatK (Ki = 0.11 ± 0.05 nM). Taken into account the increase of T-Kininogen level in inflamed rat sera, this may raise the question of the appropriateness to evaluate pharmacological hCatK inhibitors in this peculiar animal model.
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hal-03677265 , version 1 (21-07-2022)

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Paternité - Pas d'utilisation commerciale

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Fabien Lecaille, Thibault Chazeirat, Krzysztof Bojarski, Justine Renault, Ahlame Saidi, et al.. Rat cathepsin K: Enzymatic specificity and regulation of its collagenolytic activity. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2020, 1868 (2), pp.140318 -. ⟨10.1016/j.bbapap.2019.140318⟩. ⟨hal-03677265⟩
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