Abstract
Receptor tyrosine kinases are activated upon ligand-induced dimerization. Here we show that the monomeric extracellular domain of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) has a flexible structure. Binding of VEGF to membrane-distal immunoglobulin-like domains causes receptor dimerization and promotes further interaction between receptor monomers through the membrane-proximal immunoglobulin-like domain 7. By this mechanism, ligand-induced dimerization of VEGFR-2 can be communicated across the membrane, activating the intracellular tyrosine kinase domains.
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Acknowledgements
This work was supported by Swiss National Science Foundation grant 3100A0-100204 (to K.B.-H.) and US National Institutes of Health grant GM62580 (to T.W.). G.S. is a Damon Runyon Fellow, supported by the Damon Runyon Cancer Research Foundation (DRG no. 1824-04). The molecular EM facility at Harvard Medical School was established by a generous donation from the Giovanni Armenise Harvard Center for Structural Biology. We thank F. Winkler and A. Prota for critical reading of the manuscript.
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Supplementary information
Supplementary Fig. 1
Schematic representation of VEGFR-2 ECD constructs (PDF 14 kb)
Supplementary Fig. 2
Biochemical analysis of VEGFR-2 ECDs and VEGFR-2 ECD?ligand (PDF 57 kb)
Supplementary Fig. 3
Raw image of monomeric VEGFR-2 ECD in negative stain (PDF 5251 kb)
Supplementary Fig. 4
Raw image of predimerized VEGFR-2 ECD GCN4 in negative stain (PDF 4473 kb)
Supplementary Fig. 5
Raw image of negatively stained predimerized VEGFR-2 ECD GCN4 in complex with VEGF-A (PDF 4189 kb)
Supplementary Fig. 6
Raw image of negatively stained monomeric VEGFR-2 ECD in complex with VEGF-A (PDF 948 kb)
Supplementary Fig. 7
Class averages of predimerized VEGFR-2 ECD GCN4 in complex with VEGF-A (PDF 623 kb)
Supplementary Fig. 8
Class averages of monomeric VEGFR-2 ECD in complex with VEGF-A (PDF 4657 kb)
Supplementary Fig. 9
Raw image of negatively stained monomeric VEGFR-2 ECD in which immunoglobulin-like domain 7 was substituted by immunoglobulin-like domain 6 of VEGFR-1, in complex with VEGF-A (PDF 4437 kb)
Supplementary Fig. 10
Class averages of monomeric VEGFR-2 ECD in which immunoglobulin-like domain 7 was substituted by immunoglobulin-like domain 6 of VEGFR-1, in complex with VEGF-A (PDF 3462 kb)
Supplementary Table 1
Complex formation between VEGFR-2 and VEGF ligands (PDF 11 kb)
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Ruch, C., Skiniotis, G., Steinmetz, M. et al. Structure of a VEGF–VEGF receptor complex determined by electron microscopy. Nat Struct Mol Biol 14, 249–250 (2007). https://doi.org/10.1038/nsmb1202
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DOI: https://doi.org/10.1038/nsmb1202
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