Differential MMP-14 targeting by biglycan, decorin, fibromodulin, and lumican unraveled by in silico approach

• Published in: American Journal of Physiology: Cell Physiology 2023-02, Vol.324 (2), p.C353-C365
• Main Authors: Rivet, Romain, Rao, Rajas Mallenahalli, Nizet, Pierre, Belloy, Nicolas, Huber, Louise, Dauchez, Manuel, Ramont, Laurent, Baud, Stéphanie, Brézillon, Stéphane
• Format: Article
• Language: English
• Subjects: Antitumor activity; Biglycan; Cell signaling; Chondroitin Sulfate Proteoglycans - metabolism; Core protein; Decorin; Extracellular matrix; Extracellular Matrix Proteins - metabolism; Fibromodulin; Kinases; Life Sciences; Lumican; Matrix Metalloproteinase 14; Molecular Docking Simulation; Polysaccharides; Protein structure; Proteoglycans
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00429.2022

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 ( ) 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.