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 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

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 chromatography 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.

Domains: Life Sciences [q-bio]; Bioengineering; Life Sciences [q-bio]; Pharmaceutical sciences

Jean-François Gaucher, Marie Reille-Seroussi 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, 2016, 11 (12), pp.e0167755. ⟨10.1371/journal.pone.0167755⟩. ⟨hal-01439207⟩