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:

NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain

Nature volume 384, pages 638–641 (1996)Cite this article

Abstract

PROGRAMMEDcell death (apoptosis) mediated by the cytokine receptor Fas is critical for the removal of autoreactive T cells1, the mechanism of immune privilege2,3, and for maintenance of immune-system homeostasis4. Signalling of programmed cell death involves the self-association of a conserved cytoplasmic region of Fas called the death domain5–7 and interaction with another death-domain-containing protein, FADD8 (also known as MORT1)9. Although death domains are found in several proteins10, their three-dimensional structure and the manner in which they interact is unknown. Here we describe the solution structure of the Fas death domain, as determined by NMR spectroscopy. The structure consists of six antiparallel, amphi-pathic α-helices arranged in a novel fold. From the structure and from site-directed mutagenesis, we have identified the region of the death domain involved in self-association and binding to the downstream signalling partner FADD.

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

Similar content being viewed by others

References

  1. Ju, S.-T. et al. Nature 373, 444–448 (1995).

    Article  ADS  CAS  Google Scholar 

  2. Bellgrau, D. et al. Nature 377, 630–632 (1995).

    Article  ADS  CAS  Google Scholar 

  3. Griffith, T. S., Brunner, T., Fletcher, S. M., Green, D. R. & Ferguson, T. A. Science 270, 1189–1192 (1995).

    Article  ADS  CAS  Google Scholar 

  4. Nagata, S. & Goldstein, P. Science 267, 1449–1456 (1995).

    Article  ADS  CAS  Google Scholar 

  5. Tartaglia, L A., Ayres, T. M., Wong, G. H. W. & Goeddel, D. V. Cell 74, 845–853 (1993).

    Article  CAS  Google Scholar 

  6. Itoh, N. & Nagata, S. J. Biol. Chem. 268, 10932–10937 (1993).

    Google Scholar 

  7. Boldin, M. P. et al. J. Biol. Chem. 270, 387–391 (1995).

    Article  CAS  Google Scholar 

  8. Chinnaiyan, A. M., O'Rourke, K., Tewari, M. & Dixit, V. M. Cell 81, 505–512 (1995).

    Article  CAS  Google Scholar 

  9. Boldin, M. P. et al. J. Biol. Chem. 270, 7795–7798 (1995).

    Article  CAS  Google Scholar 

  10. Feinstein, E., Kimchi, A., Wallach, D., Boldin, M. P. & Varfolomeev, E. Trends Biochem. Sci. 20, 342–344 (1995).

    Article  CAS  Google Scholar 

  11. Sato, T., Irie, S., Kitada, S. & Reed, J. C. Science 268, 411–415 (1995).

    Article  ADS  CAS  Google Scholar 

  12. Kleywegt, G. J. & Jones, T. A. Structure 3, 535–540 (1995).

    Article  CAS  Google Scholar 

  13. Hsu, H., Xiong, J. & Goeddel, D. V. Cell 81, 535–540 (1995).

    Article  Google Scholar 

  14. Stanger, B. Z., Leder, P., Lee, T. L., Kim, E. & Seed, B. Cell 81, 513–523 (1995).

    Article  CAS  Google Scholar 

  15. White, K. et al. Science 264, 677–683 (1994).

    Article  ADS  CAS  Google Scholar 

  16. Goldstein, P., Marguet, D. & Depraetere, V. Cell 84, 185–186 (1995).

    Article  Google Scholar 

  17. Watanabe–Fukunaga, R., Brannan, C. I., Copeland, N. G., Jenkins, N. A. & Nagata, S. Nature 356, 314–317 (1992).

    Article  ADS  Google Scholar 

  18. Yamazaki, T., Lee, W., Arrowsmith, C. H., Muhandiram, D. R. & Kay, L. E. J. Am. Chem. Soc. 116, 11655–11666 (1994).

    Article  CAS  Google Scholar 

  19. Clore, G. M. & Gronenbom, A. M. Meth. Enzymol. 239, 349–363 (1994).

    Article  CAS  Google Scholar 

  20. Neri, D., Szyperski, T., Otting, G., Senn, H. & Wüthrich, K. Biochemistry 28, 7510–7516 (1989).

    Article  CAS  Google Scholar 

  21. Vuister, G. W. & Bax, A. J. Am. Chem. Soc. 115, 7772–7777 (1993).

    Article  CAS  Google Scholar 

  22. Kuszewski, J., Nilges, M. & Brünger, A. T. J. Biomol. NMR 2, 33–56 (1992).

    Article  CAS  Google Scholar 

  23. Brünger, A. T. X-PLOR 3.1 Manual (Yale Univ. Press, New Haven, 1992).

  24. Kim, J.-S. & Raines, R. T. Protein Sci. 2, 348–356 (1993).

    Article  CAS  Google Scholar 

  25. Dillon, P. J. & Rosen, C. A. BioTechniques 9, 298–300 (1990).

    CAS  PubMed  Google Scholar 

  26. Nilges, M., Clore, G. M. & Gronenbom, A. M. FEBS Lett. 229, 317–324 (1988).

    Article  CAS  Google Scholar 

  27. Brooks, B. R. et al. J. Comput. Chem. 4, 187–217 (1983).

    Article  CAS  Google Scholar 

  28. Carson, M. J. J. Mòl. Graph. 5, 103–106 (1987).

    Article  CAS  Google Scholar 

  29. Bradford, M. M. Anal. Biochem. 72, 248–254 (1976).

    Article  CAS  Google Scholar 

  30. Itoh, N. et al. Cell 66, 233–243 (1991).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois, 60064, USA

    Baohua Huang, Matthias Eberstadt, Edward T. Olejniczak, Robert P. Meadows & Stephen W. Fesik

Authors
  1. Baohua Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthias Eberstadt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edward T. Olejniczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert P. Meadows
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen W. Fesik
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, B., Eberstadt, M., Olejniczak, E. et al. NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature 384, 638–641 (1996). https://doi.org/10.1038/384638a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/384638a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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