期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 324, 期 2, 页码 C353-C365出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00429.2022
关键词
MMP-14; small leucine-rich proteoglycans (SLRPs); glycosylation; structure and molecular modeling
This study characterized the structure and dynamics of four SLRPs using in silico 3D modeling, and evaluated their capacity to bind to MMP-14 and regulate its activity. The results demonstrated that each SLRP exhibited significant inhibition of MMP-14 activity, which was related to the core protein conformation as well as the glycan chain structures and dynamics.
Small leucine-rich proteoglycans (SLRPs) are major regulators of extracellular matrix assembly and cell signaling. Lumican, a member of the SLRPs family, and its derived peptides were shown to possess antitumor activity by interacting directly with the catalytic domain of MMP-14 leading to the inhibition of its activity. The aim of the present report was to characterize by in silico three-dimensional (3D) modeling the structure and the dynamics of four SLRPs including their core protein and their specific polysaccharide chains to assess their capacity to bind to MMP-14 and to regulate its activity. Molecular docking experiments were performed to identify the specific amino acids of MMP-14 interacting with each of the four SLRPs. The inhibition of each SLRP (100 nM) on MMP-14 activity was measured and the constants of inhibition (Ki) were evaluated. The impact of the number of glycan chains, structures, and dynamics of lumican on the interaction with MMP-14 was assessed by molecular dynamics simulations. Molecular docking analysis showed that all SLRPs bind to MMP-14 through their concave face, but in different regions of the catalytic domain of MMP-14. Each SLRPs inhibited significantly the MMP-14 activity. Finally, molecular dynamics showed the role of glycan chains in interaction with MMP-14 and shielding effect of SLRPs. Altogether, the results demonstrated that each SLRP exhibited inhibition of MMP-14 activity. However, the differential targeting of MMP-14 by the SLRPs was shown to be related not only to the core protein conformation but also to the glycan chain structures and dynamics.
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