Structure of a VEGF–VEGF receptor complex determined by electron microscopy

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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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Figure 1: Electron microscopy of the VEGFR-2 ECD complex.
Figure 2: Ligand binding of VEGFR-2 promotes dimerization of membrane-proximal regions.

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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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Correspondence to Kurt Ballmer-Hofer.

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The authors declare no competing financial interests.

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)

Supplementary Methods (PDF 28 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) doi:10.1038/nsmb1202

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