Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons.
Fiche publication
Date publication
juillet 2017
Journal
Scientific reports
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DAUCHEZ Manuel, Pr DEDIEU Stéphane, Dr DEVY Jérôme, Dr ETIQUE Nicolas, Pr MARTINY Laurent, Pr DEVARENNE-CHARPENTIER Emmanuelle
Tous les auteurs :
Verzeaux L, Belloy N, Thevenard-Devy J, Devy J, Ferracci G, Martiny L, Dedieu S, Dauchez M, Emonard H, Etique N, Devarenne-Charpentier E
Lien Pubmed
Résumé
The tissue inhibitor of metalloproteinases-1 (TIMP-1) exerts inhibitory activity against matrix metalloproteinases and cytokine-like effects. We previously showed that TIMP-1 reduces neurite outgrowth in mouse cortical neurons and that this cytokine-like effect depends on TIMP-1 endocytosis mediated by the low-density lipoprotein receptor-related protein-1 (LRP-1). To gain insight into the interaction between TIMP-1 and LRP-1, we considered conformational changes that occur when a ligand binds to its receptor. TIMP-1 conformational changes have been studied using biomolecular simulations, and our results provide evidence for a hinge region that is critical for the protein movement between the N- and C-terminal TIMP-1 domains. In silico mutants have been proposed on residues F12 and K47, which are located in the hinge region. Biological analyses of these mutants show that F12A or K47A mutation does not alter MMP inhibitory activity but impairs the effect of TIMP-1 on neurite outgrowth. Interestingly, these mutants bind to LRP-1 but are not endocytosed. We conclude that the intrinsic dynamics of TIMP-1 are not involved in its binding to LRP-1 but rather in the initiation of endocytosis and associated biological effects.
Mots clés
Amino Acids, genetics, Animals, Cells, Cultured, Endocytosis, Mice, Molecular Dynamics Simulation, Mutant Proteins, genetics, Neurons, metabolism, Protein Conformation, Protein Interaction Mapping, Receptors, LDL, metabolism, Tissue Inhibitor of Metalloproteinase-1, genetics, Tumor Suppressor Proteins, metabolism
Référence
Sci Rep. 2017 Jul;7(1):5375