Role of Glycosaminoglycans in Procathepsin B Maturation: Molecular Mechanism Elucidated by a Computational Study.
Role of Glycosaminoglycans in Procathepsin B Maturation: Molecular Mechanism Elucidated by a Computational Study.
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糖胺聚糖在proathepsin B成熟中的作用：通过计算研究阐明的分子机制。
DOI：
10.1021/acs.jcim.0c00023
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发表时间：
2020-04-27
影响因子：
5.6
通讯作者：
Samsonov SA
中科院分区：
文献类型：
--
作者：
Bojarski KK;Karczyńska AS;Samsonov SA
组织蛋白酶原是组织蛋白酶的无活性、未成熟形式，主要是存在于细胞外基质（ECM）和溶酶体中的半胱氨酸蛋白酶，其在各种生物过程如骨吸收或细胞内蛋白水解中起关键作用。组织蛋白酶的酶活性可以由糖胺聚糖（GAG）介导，糖胺聚糖是ECM中发现的长的无分支周期性带负电荷的多糖，其参与许多生物过程，如抗凝、血管生成和组织再生。除了对成熟组织蛋白酶的已知作用之外，GAG还可以介导组织蛋白酶原，特别是组织蛋白酶原B的成熟过程。然而，这种调解在分子水平上的详细机制仍然是未知的。在这项研究中，我们的目的是第一次解开的作用，糖胺聚糖在这一过程中使用计算方法。我们严格地分析了前组织蛋白酶B-GAG复合物的动力学，能量学和潜在的变构调节。我们发现，糖胺聚糖可以稳定的构象的蛋白酶原B结构的活性位点的基板，并得出结论，糖胺聚糖最有可能结合蛋白酶原B，一旦酶原采取酶活性构象。我们的数据提供了一个新的机制观点的成熟过程中的蛋白酶原B，而这里阐述的方法可能是有用的，以研究其他蛋白酶原。此外，我们的数据可以作为一个合理的指导，在体内和体外尚未表征的蛋白酶原-GAG系统的实验工作。
Procathepsins are an inactive, immature form of cathepsins, predominantly cysteine proteases present in the extracellular matrix (ECM) and in lysosomes that play a key role in various biological processes such as bone resorption or intracellular proteolysis. The enzymatic activity of cathepsins 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 the 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, we aimed to unravel the role of GAGs in this process using computational approaches. We rigorously analyzed procathepsin B–GAG complexes in terms of their dynamics, energetics, and potential allosteric regulation. We revealed that GAGs can stabilize the conformation of the procathepsin B structure with the active site accessible for the substrate and concluded that GAGs most probably bind to procathepsin B once the zymogen adopts the enzymatically active conformation. Our data provided a novel mechanistic view of the maturation process of procathepsin B, while the approaches elaborated here might be useful to study other procathepsins. Furthermore, our data can serve as a rational guide for experimental work on procathepsin–GAG systems that are not characterized in vivo and in vitro yet.
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影响因子：
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