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.

  • Letter
  • Published:

Flt3 ligand structure and unexpected commonalities of helical bundles and cystine knots

Nature Structural Biology volume 7, pages 486–491 (2000)Cite this article

Abstract

Human Flt3 ligand (Flt3L) stimulates early hematopoiesis by activating a type III tyrosine kinase receptor on primitive bone marrow stem cells. The crystal structure of soluble Flt3L reveals that it is a homodimer of two short chain α-helical bundles. Comparisons of structure-function relationships of Flt3L with the homologous hematopoietic cytokines macrophage colony stimulating factor (MCSF) and stem cell factor (SCF) suggest that they have a common receptor binding mode that is distinct from the paradigm derived from the complex of growth hormone with its receptor. Furthermore, we identify recognition features common to all helical and cystine-knot protein ligands that activate type III tyrosine kinase receptors, and the closely related type V tyrosine kinase receptors.

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: Classification of cytokines according to their structure and receptor.
Figure 2: Structure of Flt3L.
Figure 3: Comparisons of Flt3L, MCSF, SCF sequences and mutational data with each other and with the GH paradigm.
Figure 4: Physical comparison of ligands that associate with PDGFR-like receptors and mapping of known mutagenesis data to their surfaces to allow a direct comparison of known and putative receptor interaction sites9,10,13,15,24,27,28,30,31,33.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Ogawa, M. Blood 81, 2844–2853 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Heldin, C.H. Cell 80, 213–223 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Fichelson, S. Eur. Cytokine Network 9, 7–22 (1998).

    CAS  Google Scholar 

  4. Lyman, S.D. et al. Blood 83, 2795–2801 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Hannum, C. et al. Nature 368, 643–648 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Escobar, S., Brasel, K., Anderberg, R. & Lyman, S.D. Blood 86, 21a (1995).

    Google Scholar 

  7. Bazan, J.F. Cell 65, 9–10 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Van der Geer, P., Hunter, T., Lindberg, R.A. Annu. Rev. Cell. Biol. 10, 251–337 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Pandit, J. et al. Science 258, 1358–1362 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Sprang, S.R. & Bazan, J.F. Curr. Opin. Struct. Biol. 3, 815–827 (1993).

    Article  CAS  Google Scholar 

  12. Kaushansky, K. & Karplus, P.A. Blood 82, 3229–3240 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Taylor, E.W., Fear, A.L., Bohm, A., Kim, S.-H. & Koths, K. J. Biol. Chem. 269, 31171–31117 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Mott, H.R. & Campbell, I.D. Curr. Opin. Struct. Biol. 5, 114–121 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Matous, J.V., Langley, K. & Kaushansky, K. Blood 88, 437–444 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Mendiaz, E.A. et al. Eur. J. Biochem. 239, 842–849 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Menziani, M.C., Fanelli, F. & De Benedetti, P.G. Proteins 26, 42–54 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Simpson, R.J., Hammacher, A., Smith, D.K., Matthews, J.M. & Ward, L.D. Protein Sci. 6, 929–955 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. de Vos, A.M., Ultsch, M. & Kossiakoff, A.A. Science 255, 306–312, 1992.

  20. Walter, M.R. et al. Nature 376, 230–235 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Syed, R.S. et al. Nature 395, 511–516 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Hage, T., Sebald, W. & Reinemer, P. Cell 97, 271–281 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Rozwarski, D.A. et al. Structure 2, 159–173 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Graddis, T.J. et al. J. Biol. Chem. 273, 17626–17633 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Banner, D.W. et al. Cell 73, 431–445 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Vigers, G.P.A., Anderson, L.J., Caffes, P. & Brandhuber, B.J. Nature 386, 190–194 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Hsu, Y.R. et al. Biochemistry 37, 2251–2262 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Oefner, C., D'Arcy, A., Winkler, F.K., Eggimann, B. & Hosang, M. EMBO J. 11, 3921–3926 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Muller, Y.A., Christinger, H.W., Wells, Keyt, B.A. & de Vos, A.M. Structure 5, 1325–1338 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Östman, A., Andersson, M., Hellman, U. & Heldin, C.H. J. Biol. Chem. 266, 10073–10077 (1991).

    Article  PubMed  Google Scholar 

  31. Clements, J.M. et al. EMBO J. 10, 4113–4120 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Keyt, B.A. et al. J. Biol. Chem. 271, 5638–5646 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Schilling, D. et al. Biochem. J. 333, 637–644 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nicola, N.A. In Guidebook to cytokines and their receptors. (ed. Nicola, N.A.) 1–7 (Oxford University Press, New York; 1994).

    Google Scholar 

  35. DeLano, W.L., Ultsch, M.H., de Vos, A.M., Wells, J.A. Science 287, 1279–1283 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Otwinowski, Z, Minor, W. Methods Enzymol. 276, 307–326 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Furey, W. & Swaminathan, S. Methods Enzymol. 277, 590–620 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Brünger, A.T. X-PLOR version 3.1: a system for X-ray crystallography and NMR. (Yale University Press, New Haven, Connecticut; 1992).

    Google Scholar 

  39. Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. J. Appl. Crystallogr. 26, 283–291 (1983).

    Article  Google Scholar 

  40. Kraulis, Per J. J. Appl. Crystallogr. 24, 946–950 (1991).

    Article  Google Scholar 

  41. Merritt, E.A. & Bacon, D.J. Methods Enzymol. 277, 505–524 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Sack, J.S. Methods Enzymol. 277, 158–173 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Nicholls, B., Sharp, K.A. & Honig, B. Biophys. J. 64, 166–170 (1993).

    Google Scholar 

  44. Kabsch, W. & Sander, C. Biopolymers 22, 2577–2637 (1983).

    Article  CAS  PubMed  Google Scholar 

  45. Miller, S., Janin, J., Lesk, A.M. & Chothia, C. J. Mol. Biol. 196, 641–656 (1987).

    Article  CAS  PubMed  Google Scholar 

  46. Hsu, Y.R. et al. J. Biol. Chem. 272, 6406–6415 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Diederichs, K. & Karplus, P.A. Nature Struct. Biol. 4, 269–274 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank the staff of MacCHESS for help with data collection, and S.-H. Kim for the complete atomic coordinates of MCSF. This work was supported in part by a NSF grant to P.A.K. and a fellowship from the International Center for Diffraction Data to S.N.S.

Author information

Author notes

  1. Savvas N. Savvides

    Present address: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, 63110, USA

Authors and Affiliations

  1. Program in Biophysics, Cornell University, Ithaca, 14853, New York, USA

    Savvas N. Savvides & P. Andrew Karplus

  2. Department of Biochemistry and Biophysics, Oregon State University, Corvallis, 97331, Oregon, USA

    Savvas N. Savvides & P. Andrew Karplus

  3. AMGEN, Thousand Oaks, 91320-1789, California, USA

    Tom Boone

Authors
  1. Savvas N. Savvides
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tom Boone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Andrew Karplus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Andrew Karplus.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Savvides, S., Boone, T. & Andrew Karplus, P. Flt3 ligand structure and unexpected commonalities of helical bundles and cystine knots. Nat Struct Mol Biol 7, 486–491 (2000). https://doi.org/10.1038/75896

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/75896

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