https://scholars.lib.ntu.edu.tw/handle/123456789/597967
標題: | Computational insights into the substrate recognition mechanism of cartilage extracellular matrix degradation | 作者: | Lai Y.-Y Li D SHU-WEI CHANG |
關鍵字: | ADAMTS-5;Aggrecan;Degradation;Extracellular matrix;Molecular dynamics;Osteoarthritis;Binding sites;Bioinformatics;Cartilage;Collagen;Computational chemistry;Joints (anatomy);A disintegrin and metalloproteinase with thrombospondin motif-5;Cartilage extracellular matrixes;Cleavage sites;Disintegrins;Extracellular matrices;Extracellular matrix degradation;Metalloproteinases;Substrate recognition;Thrombospondin motifs;Glycoproteins;aggrecan;aggrecanase 2;amino acid;proteoglycan;arthropathy;Article;binding affinity;cartilage degeneration;catalysis;computer model;enzyme active site;enzyme structure;extracellular matrix;human;hydrogen bond;hydrolysis;mechanical stimulation;molecular mechanics;osteoarthritis | 公開日期: | 2021 | 卷: | 19 | 起(迄)頁: | 5535-5545 | 來源出版物: | Computational and Structural Biotechnology Journal | 摘要: | Articular cartilage is connective tissue that forms a slippery load-bearing joint surface between bones. With outstanding mechanical properties, it plays an essential role in cushioning impact and protecting the ends of bones. Abnormal mechanical stimulation, such as repetitive overloading or chondral injury, induces excessive cartilage extracellular matrix (ECM) degradation, leading to osteoarthritis and other joint disorders. A disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is an aggrecanase that dominates the catalysis of aggrecan, the major proteoglycan in the cartilage ECM. Intriguingly, unlike its critical cleavage site Glu373–374Ala, another potential cleavage site, Glu419-420Ala, composed of the same amino acids in the aggrecan interglobular domain, is not a major cleavage site. It remains unclear how ADAMTS-5 distinguishes between them and hydrolyzes the correct scissile bonds. This research introduces a bottom-up in silico approach to reveal the molecular mechanism by which ADAMTS-5 recognizes the cleavage site on aggrecan. It is hypothesized that the sequence in the vicinity assists ADAMTS-5 in positioning the cleavage site. Specific residues were found to serve as binding sites, helping aggrecan bind more stably and fit into the enzyme better. The findings provide insight into the substrate binding and recognition mechanism for cartilage ECM degradation from a brand new atomic-scale perspective, laying the foundation for prophylaxis and treatment of related joint diseases. ? 2021 The Authors |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85116874531&doi=10.1016%2fj.csbj.2021.10.002&partnerID=40&md5=2a83c5c2ef1550ea0921a1e979474ca6 https://scholars.lib.ntu.edu.tw/handle/123456789/597967 |
ISSN: | 20010370 | DOI: | 10.1016/j.csbj.2021.10.002 |
顯示於: | 土木工程學系 |
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