Biophysical Studies of the Induced Dimerization of Human VEGF Receptor 1 Binding Domain by Divalent Metals Competing with VEGF-A

Jean-François Gaucher 1 Marie Reille-Seroussi 2 Nathalie Gagey-Eilstein 2 Sylvain Broussy 2 Pascale Coric 1 Bili Seijo 1 Marie-Bernard Lascombe 1 Benoit Gautier 2 Wang-Quing Liu 2 Florent Huguenot 2 Nicolas Inguimbert 3 Serge Bouaziz 1 Michel Vidal 2, 4 Isabelle Broutin 1
1 LCRB - UMR 8015 - Laboratoire de cristallographie et RMN biologiques
2 COMETE - UMR 8638 - Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale
3 CRIOBE - Centre de recherches insulaires et observatoire de l'environnement
4 PMC - UMR_S 648 - Pharmacochimie Moléculaire et Cellulaire
Abstract : Angiogenesis is tightly regulated through the binding of vascular endothelial growth factors (VEGFs) to their receptors (VEGFRs). In this context, we showed that human VEGFR1 domain 2 crystallizes in the presence of Zn 2+ , Co 2+ or Cu 2+ as a dimer that forms via metal- ion interactions and interlocked hydrophobic surfaces. SAXS, NMR and size exclusion chro- matography analyses confirm the formation of this dimer in solution in the presence of Co 2+ , Cd 2+ or Cu 2+ . Since the metal-induced dimerization masks the VEGFs binding surface, we investigated the ability of metal ions to displace the VEGF-A binding to hVEGFR1: using a competition assay, we evidenced that the metals displaced the VEGF-A binding to hVEGFR1 extracellular domain binding at micromolar level.
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Jean-François Gaucher, Marie Reille-Seroussi, Nathalie Gagey-Eilstein, Sylvain Broussy, Pascale Coric, et al.. Biophysical Studies of the Induced Dimerization of Human VEGF Receptor 1 Binding Domain by Divalent Metals Competing with VEGF-A. PLoS ONE, Public Library of Science, 2016, ⟨10.1371/journal. pone.0167755⟩. ⟨hal-01439207⟩

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