Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation
Copyright policy )Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation
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.
- University of Basel Switzerland
- Helsinki University Hospital Finland
- Institute for Molecular Medicine Finland Finland
- University of Helsinki Finland
- Paul Scherrer Institute Switzerland
Models, Molecular, SX20 Research, Technology and Development Projects, Receptor tyrosine kinase, Molecular Sequence Data, Vascular Endothelial Growth Factor C, Signal transduction, Crystallography, X-Ray, Ligands, Binding, Competitive, SX00 SystemsX.ch, Scattering, Small Angle, Humans, Amino Acid Sequence, 1000 Multidisciplinary, Binding Sites, Sequence Homology, Amino Acid, Vascular Endothelial Growth Factor Receptor-3, Protein Structure, Tertiary, Microscopy, Electron, Multiprotein Complexes, Mutation, SX03 CINA, 570 Life sciences; biology, Thermodynamics, Electrophoresis, Polyacrylamide Gel, Protein Multimerization, Protein Binding
Models, Molecular, SX20 Research, Technology and Development Projects, Receptor tyrosine kinase, Molecular Sequence Data, Vascular Endothelial Growth Factor C, Signal transduction, Crystallography, X-Ray, Ligands, Binding, Competitive, SX00 SystemsX.ch, Scattering, Small Angle, Humans, Amino Acid Sequence, 1000 Multidisciplinary, Binding Sites, Sequence Homology, Amino Acid, Vascular Endothelial Growth Factor Receptor-3, Protein Structure, Tertiary, Microscopy, Electron, Multiprotein Complexes, Mutation, SX03 CINA, 570 Life sciences; biology, Thermodynamics, Electrophoresis, Polyacrylamide Gel, Protein Multimerization, Protein Binding
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).104 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!