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:

von Willebrand factor conformation and adhesive function is modulated by an internalized water molecule

Nature Structural Biology volume 7, pages 881–884 (2000)Cite this article

Abstract

Platelet participation in hemostasis and arterial thrombosis requires the binding of glycoprotein (GP) Ibα to von Willebrand factor (vWF). Hemodynamic forces enhance this interaction, an effect mimicked by the substitution I546V in the vWF A1 domain. A water molecule becomes internalized near the deleted Ile methyl group. The change in hydrophobicity of the local environment causes positional changes propagated over a distance of 27 Å. As a consequence, a major reorientation of a peptide plane occurs in a surface loop involved in GP Ibα binding. This distinct vWF conformation shows increased platelet adhesion and provides a structural model for the initial regulation of thrombus formation.

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: Location of the I546V mutation and its effects on platelet adhesion.
Figure 2: Structural changes in the mutant A1 domain.
Figure 3: Stereo representation of a partial surface of the vWF A1 domain wild type and I546V mutant.
Figure 4: Platelet adhesion to mutant vWF A1 domain fragments.

Similar content being viewed by others

References

  1. Ruggeri, Z.M. In von Willebrand factor and the mechanisms of platelet function. (ed., Ruggeri, Z.M.), 33–77 (Springer, Berlin; 1998).

    Google Scholar 

  2. Savage, B., Saldivar, E. & Ruggeri, Z.M. Cell 84, 289– 297 (1996).

    Article  CAS  Google Scholar 

  3. Savage, B., Almus-Jacobs, F. & Ruggeri, Z.M. Cell 94, 657– 666 (1998).

    Article  CAS  Google Scholar 

  4. Ruggeri, Z.M., Dent, J.A. & Saldivar, E. Blood 94, 172– 178 (1999).

    CAS  PubMed  Google Scholar 

  5. Tschopp, T.B., Weiss, H.J. & Baumgartner, H.R. J. Lab. Clin. Med. 83, 296– 300 (1974).

    CAS  PubMed  Google Scholar 

  6. Fuster, V., Badimon, L., Badimon, J.J. & Chesebro, J.H. N. Engl. J. Med. 326, 242–250 (1992).

    Article  CAS  Google Scholar 

  7. Fuster, V., Badimon, L., Badimon, J.J. & Chesebro, J.H. N. Engl. J. Med. 326, 310–318 (1992).

    Article  CAS  Google Scholar 

  8. Miyata, S. & Ruggeri, Z.M. J. Biol. Chem. 274, 6586–6593 (1999).

    Article  CAS  Google Scholar 

  9. Marchese, P., Saldivar, E., Ware, J. & Ruggeri, Z.M. Proc. Natl. Acad. Sci. USA 96, 7837–7842 (1999).

    Article  CAS  Google Scholar 

  10. Ware, J. et al. Proc. Natl. Acad. Sci. USA 88, 2946– 2950 (1991).

    Article  CAS  Google Scholar 

  11. Ruggeri, Z.M., Pareti, F.I., Mannucci, P.M., Ciavarella, N. & Zimmerman, T.S. N. Engl. J. Med. 302, 1047–1051 ( 1980).

    Article  CAS  Google Scholar 

  12. Ruggeri, Z.M. & Zimmerman, T.S. J. Clin. Invest. 65, 1318–1325 ( 1980).

    Article  CAS  Google Scholar 

  13. De Marco, L., Girolami, A., Zimmerman, T.S. & Ruggeri, Z.M. Proc. Natl. Acad. Sci. USA 82, 7424– 7428 (1985).

    Article  CAS  Google Scholar 

  14. Celikel,R., et al. Nature Struct. Biol. 5, 189– 194 (1998).

    Article  CAS  Google Scholar 

  15. Emsley, J., Cruz, M., Handin, R. & Liddington, R. J. Biol. Chem. 273, 10396–10401 ( 1998).

    Article  CAS  Google Scholar 

  16. Cruz, M.A. et al. J. Biol. Chem. 275, 19098– 19105 (2000).

    Article  CAS  Google Scholar 

  17. Rabinowitz, I., et al. Proc. Natl. Acad. Sci. USA 89, 9846 –9849 (1992).

    Article  CAS  Google Scholar 

  18. Xu, J., Baase, W.A., Baldwin, E. & Matthews, B.W. Protein Sci. 7, 158–177 (1998).

    Article  CAS  Google Scholar 

  19. Blaber, M. et al. Biochemistry 32, 11363– 11373 (1993).

    Article  CAS  Google Scholar 

  20. Vetter, I.R., et al. Protein Sci. 5, 2399– 2415 (1996).

    Article  CAS  Google Scholar 

  21. Komives, E.A., et al. Biochemistry 34, 13612– 13621 (1995).

    Article  CAS  Google Scholar 

  22. Zhang, Z., et al. Biochemistry 38, 4389– 4397 (1999).

    Article  CAS  Google Scholar 

  23. Miyata, S., Goto, S., Federici, A.B., Ware, J. & Ruggeri, Z.M. J. Biol. Chem. 271 , 9046–9053 (1996).

    Article  CAS  Google Scholar 

  24. Federici, A.B., et al. Thromb. Haemost. 78, 1132– 1137 (1997).

    Article  CAS  Google Scholar 

  25. Brünger, A.T. X-PLOR crystallographic program suite (Version 3.851). (Yale University Press, New Haven, Connecticut; 1996).

    Google Scholar 

  26. Brünger, A.T., et al. Acta Crystallogr. D 54, 905– 921 (1998).

    Article  Google Scholar 

  27. Usami, S., Chen, H.H., Zhao, Y., Chien, S. & Skalak, R. Ann. Biomed. Eng. 21, 77–83 (1993).

    Article  CAS  Google Scholar 

  28. Esnouf, R.M. J. Mol. Graph Model 15, 132–134 (1997).

    Article  CAS  Google Scholar 

  29. Sanner, M.F., Olson,A.J. & Spehner, J.C. Biopolymers 38, 305– 320 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Ware for his assistance in the preparation of recombinant proteins and valuable suggestions during this entire project. We are also indebted to J.R. Roberts and R.A. McClintock for the expression and purification of vWF fragments and NMC-4 Fab; to J.A. Dent for assistance with the flow studies; to R. Habermann for help with image analysis and video editing; to U. Sen for assistance in computation; to M. Pique for preparing Fig. 4; and to B. Mathews for discussing the lysozyme mutants. This work was supported by National Institutes of Health grants and by the Rose and Sam Stein fund. The X-ray diffraction facilities were provided by N.H. Xuong at University of California, San Diego and the Stanford Synchrotron Radiation Laboratory.

Author information

Author notes

  1. Zaverio M. Ruggeri and Kottayil I. Varughese: Joint senior authors.

Authors and Affiliations

  1. Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine and Department of Vascular Biology, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, 92037 , California, USA

    Reha Celikel, Zaverio M. Ruggeri & Kottayil I. Varughese

Authors
  1. Reha Celikel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zaverio M. Ruggeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kottayil I. Varughese
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zaverio M. Ruggeri or Kottayil I. Varughese.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Celikel, R., Ruggeri, Z. & Varughese, K. von Willebrand factor conformation and adhesive function is modulated by an internalized water molecule. Nat Struct Mol Biol 7, 881–884 (2000). https://doi.org/10.1038/79639

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/79639

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