Title : Structural and mechanistic insights into
VEGF receptor 3 ligand binding and activation
Abstract :
- Vascular endothelial growth factors ( VEGFs ) and their receptors ( VEGFRs ) are key drivers of blood and lymph vessel formation in development, but also in several pathological processes
- VEGF-C signaling through VEGFR-3 promotes lymphangiogenesis, which is a clinically relevant target for treating lymphatic insufficiency and for blocking tumor angiogenesis and metastasis
- The extracellular domain of VEGFRs consists of seven Ig homology domains ; domains 1-3 (D1-3) are responsible for ligand binding, and the membrane-proximal domains 4-7 (D4-7) are involved in structural rearrangements essential for receptor dimerization and activation
- Here we analyzed the crystal structures of VEGF-C in complex with VEGFR-3 domains D1-2 and of the VEGFR-3 D4-5 homodimer
- The structures revealed a conserved ligand-binding interface in D2 and a unique mechanism for VEGFR dimerization and activation, with homotypic interactions in D5
- Mutation of the conserved residues mediating the D5 interaction ( Thr446 and Lys516 ) and the D7 interaction ( Arg737 ) compromised VEGF-C induced VEGFR-3 activation
- A thermodynamic analysis of VEGFR-3 deletion mutants showed that D3, D4-5, and D6-7 all contribute to ligand binding
- A structural model of the VEGF-C/ VEGFR-3 D1-7 complex derived from small-angle X-ray scattering data is consistent with the homotypic interactions in D5 and D7
- Taken together, our data show that ligand-dependent homotypic interactions in D5 and D7 are essential for VEGFR activation, opening promising possibilities for the design of VEGFR-specific drugs