logo amu logo cnrs

UMR 7286 - Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille

Plates-formes PFRN

Accueil > Bibliographie > Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for (...)

Intrinsic dynamics study identifies two amino acids of (...)

Sci Rep. 2017 Jul ;7(1):5375
Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons.
Verzeaux L, Belloy N, Thevenard-Devy J, Devy J, Ferracci G, Martiny L, Dedieu S, Dauchez M, Emonard H, Etique N, Devarenne-Charpentier E.

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.

PubMed

Le CRN2M en chiffres

  • 20 Chercheurs
  • 19 Enseignants Chercheurs
  • 39 ITAs et IATOs
  • 3 Post-Docs
  • 5 Docs
  • 4 Étudiants de Master

    Ils nous font confiance

  • logo amu
  • logo cnrs
  • logo inserm
  • logo AP-HM
  • logo Galderma
  • logo Ipsem
  • logo Novartis
  • logo Pfizer
  • logo Fédération pour la Recherche sur le Cerveau
  • logo Fondation pour la Recherche Medical en France
  • logo IBiSA
  • logo Europe programme FEDER
  • logo Agence Nationale de la Recherche