Differential MMP-14 Targeting by Biglycan, Decorin, Fibromodulin and Lumican Unraveled by In Silico Approach.

Félicitations à l’équipe de Stéphane Brezillon et ses collaborateurs pour leur nouvelle publication dans « Am J Physiol Cell Physiol. » sur le rôle des SLRP et de leurs chaines de GAG dans la régulation de l’activité de MMP-14 !

Rivet R, Rao RM, Nizet P, Belloy N, Huber L, Dauchez M, Ramont L, Baud S, Brézillon S. Am J Physiol Cell Physiol. 2022 Dec 19. doi: 10.1152/ajpcell.00429.2022. Online ahead of print.PMID: 36534501

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 possess anti-tumor activity by interacting directly with the catalytic domain of MMP-14 leading to the inhibition of its activity. The aim of this report was to characterize by in silico 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 (100nM) on MMP-14 activity 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.