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The Role of Glycosaminoglycans in Procathepsin B Maturation - Molecular Mechanism Elucidated by a Computational Study.

08:00 EDT 10th March 2020 | BioPortfolio

Summary of "The Role of Glycosaminoglycans in Procathepsin B Maturation - Molecular Mechanism Elucidated by a Computational Study."

Procathepsins are inactive, immature form of cathepsins, predominantly cysteine proteases present in extracellular matrix (ECM) and in lysosomes that play a key role in a various biological processes such as bone resorption or intracellular proteolysis. Enzymatic activity of 1cathepsins can be mediated by glycosaminoglycans (GAGs) - long unbranched periodic negatively charged polysaccharides found in ECM that take part in many biological processes such as anticoagulation, angiogenesis and tissue regeneration. In addition to the known effects on mature cathepsins, GAGs can mediate maturation process of procathepsins, in particular procathepsin B. However, the detailed mechanism of this mediation at the molecular level is still unknown. In this study, for the first time aimed to unravel the role of GAGs in this process using computational approaches. We rigorously analysed procathepsin B-GAG complexes in terms of their dynamics, energetics and potential allosteric regulation. We revealed that GAGs can stabilize the conformation of procathepsin B structure with the active site accessible for the substrate, and concluded that GAGs most probably bind to the procathepsin B once the zymogen adopts the enzymatically active conformation. Our data provided a novel mechanistic view on the maturation process of procathepsin B, while the elaborated here approaches might be useful to study other procathepsins. Furthermore, our data can serve as a rational guide for experimental work on procathepsin-GAG systems that were not characterized in vivo and in vitro yet.

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This article was published in the following journal.

Name: Journal of chemical information and modeling
ISSN: 1549-960X
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