Rat cathepsin K: enzymatic specificity and regulation of its collagenolytic activity
Fabien Lecaille , Thibault Chazeirat , Krzysztof Bojarski , Justine Renault , Ahlame Saidi , V. Gangadhara N.V. Prasad , Sergey Samsonov , Gilles Lalmanach
AbstractHuman cathepsin K (hCatK), which is highly expressed in osteoclasts, has the noteworthy ability to cleave type Iand II collagens in their helical domain. Its collagenase potency depends strictly on the formation of an oligo-meric complex with chondroitin 4-sulfate (C4-S). Accordingly, hCatK is a pivotal protease involved in boneresorption and is an attractive target for the treatment of osteoporosis. As rat is a common animal model for theevaluation of hCatK inhibitors, we conducted a comparative analysis of rat CatK (rCatK) and hCatK, which sharea high degree of identity (88%) and similarity (93%). The pH activity profile of both enzymes displayed a similarbell-shaped curve (optimal pH: 6.4). Presence of Ser134 and Val160 in the S2 pocket of rCatK instead of Ala andLeu 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) andtype II (articular joint) rat collagens. Structure-based computational analyses (electrostatic potential, moleculardocking, molecular dynamics, free energy calculations) sustained that the C4-S mediated collagenolytic activityof 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 theappropriateness to evaluate pharmacological hCatK inhibitors in this peculiar animal model.
|Journal series||Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, [Biochimica et Biophysica Acta - Proteins and Proteomics], ISSN 1570-9639, (N/A 70 pkt)|
|Publication size in sheets||0.5|
|Keywords in English||Cathepsin K, chondroitin 4-sulfate, collagen, cysteine protease, protein-glycosaminoglycan interactions, T-kininogen|
|ASJC Classification||; ; ;|
|License||Repository; author's final; ; with publication|
|Score||= 70.0, 28-01-2020, ArticleFromJournal|
|Publication indicators||: 2018 = 0.795; : 2018 = 2.54 (2) - 2018=2.703 (5)|
|Licencja||Utwór jest udostępniany na licencji Creative Commons Uznanie autorstwa-Użycie niekomercyjne-Na tych samych warunkach 4.0 Międzynarodowe (CC BY-NC-SA 4.0) https://creativecommons.org/licenses/by-nc-sa/4.0/|
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