Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

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

Nature Structural & Molecular Biology volume 14, pages 249–250 (2007)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Hubbard, S.R. Nat. Rev. Mol. Cell Biol. 5, 464–471 (2004).

    Article  CAS  Google Scholar 

  2. Schlessinger, J. Science 300, 750–752 (2003).

    Article  CAS  Google Scholar 

  3. Olsson, A.K., Dimberg, A., Kreuger, J. & Claesson-Welsh, L. Nat. Rev. Mol. Cell Biol. 7, 359–371 (2006).

    Article  CAS  Google Scholar 

  4. Christinger, H.W., Fuh, G., de Vos, A.M. & Wiesmann, C. J. Biol. Chem. 279, 10382–10388 (2003).

    Article  Google Scholar 

  5. Wiesmann, C. et al. Cell 91, 695–704 (1997).

    Article  CAS  Google Scholar 

  6. Muller, Y.A. et al. Proc. Natl. Acad. Sci. USA 94, 7192–7197 (1997).

    Article  CAS  Google Scholar 

  7. Pieren, M. et al. J. Biol. Chem. 281, 19578–19587 (2006).

    Article  CAS  Google Scholar 

  8. Shinkai, A. et al. J. Biol. Chem. 273, 31283–31288 (1998).

    Article  CAS  Google Scholar 

  9. Fuh, G., Li, B., Crowley, C., Cunningham, B. & Wells, J.A. J. Biol. Chem. 273, 11197–11204 (1998).

    Article  CAS  Google Scholar 

  10. Skiniotis, G., Boulanger, M.J., Garcia, K.C. & Walz, T. Nat. Struct. Mol. Biol. 12, 545–551 (2005).

    Article  CAS  Google Scholar 

  11. Blechman, J.M. et al. Cell 80, 103–113 (1995).

    Article  CAS  Google Scholar 

  12. Shulman, T., Sauer, F.G., Jackman, R.M., Chang, C.N. & Landolfi, N.F. J. Biol. Chem. 272, 17400–17404 (1997).

    Article  CAS  Google Scholar 

  13. Omura, T., Heldin, C.H. & Ostman, A. J. Biol. Chem. 272, 12676–12682 (1997).

    Article  CAS  Google Scholar 

  14. Barleon, B. et al. J. Biol. Chem. 272, 10382–10388 (1997).

    Article  CAS  Google Scholar 

  15. Tao, Q., Backer, M.V., Backer, J.M. & Terman, B.I. J. Biol. Chem. 276, 21916–21923 (2001).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Claudia Ruch and Georgios Skiniotis: These authors contributed equally to this work.

Authors and Affiliations

  1. Paul Scherrer Institut, Biomolecular Research, Molecular Cell Biology, Villigen-PSI, CH-5232, Switzerland

    Claudia Ruch & Kurt Ballmer-Hofer

  2. Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Georgios Skiniotis & Thomas Walz

  3. Paul Scherrer Institut, Biomolecular Research, Structural Biology, Villigen-PSI, CH-5232, Switzerland

    Michel O Steinmetz

Authors
  1. Claudia Ruch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Georgios Skiniotis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michel O Steinmetz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Walz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kurt Ballmer-Hofer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kurt Ballmer-Hofer.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb1202

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing