DNA binding is required for the apoptogenic action of apoptosis inducing factor (original) (raw)

Nature Structural Biology volume 9, pages 680–684 (2002)Cite this article

Abstract

The execution of apoptosis or programmed cell death comprises both caspase-dependent and caspase-independent processes. Apoptosis inducing factor (AIF) was identified as a major player in caspase-independent cell death. It induces chromatin condensation and initial DNA cleavage via an unknown molecular mechanism. Here we report the crystal structure of human AIF at 1.8 Å resolution. The structure reveals the presence of a strong positive electrostatic potential at the AIF surface, although the calculated isoelectric point for the entire protein is neutral. We show that recombinant AIF interacts with DNA in a sequence-independent manner. In addition, in cells treated with an apoptotic stimulus, endogenous AIF becomes co-localized with DNA at an early stage of nuclear morphological changes. Structure-based mutagenesis shows that DNA-binding defective mutants of AIF fail to induce cell death while retaining nuclear translocation. The potential DNA-binding site identified from mutagenesis also coincides with computational docking of a DNA duplex. These observations suggest that AIF-induced nuclear apoptosis requires a direct interaction with DNA.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

USD 39.95

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

Additional access options:

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Zamzami, N. & Kroemer, G. Nature Rev. Mol. Cell Biol. 2, 67–71 (2001).
    Article CAS Google Scholar
  2. Wang, X. Genes Dev. 15, 2922–2933 (2001).
    CAS PubMed Google Scholar
  3. Susin, S.A. et al. Nature 397, 441–446 (1999).
    Article CAS PubMed Google Scholar
  4. Green, D.R. Cell 94, 695–698 (1998).
    Article CAS PubMed Google Scholar
  5. Joza, N. et al. Nature 410, 549–554 (2001).
    Article CAS PubMed Google Scholar
  6. Susin, S.A. et al. J. Exp. Med. 192, 571–580 (2000).
    Article CAS PubMed PubMed Central Google Scholar
  7. Arnoult, D. et al. Mol. Biol. Cell 12, 3016–3030 (2001).
    Article CAS PubMed PubMed Central Google Scholar
  8. Miramar, M.D. et al. J. Biol. Chem. 276, 16391–16398 (2001).
    Article CAS PubMed Google Scholar
  9. Mate, M.J. et al. Nature Struct. Biol. 9, 442–446 (2002).
    Article CAS PubMed Google Scholar
  10. Holm, L. & Sander, C. Trends Biochem. Sci. 20, 478–480 (1995).
    Article CAS PubMed Google Scholar
  11. Senda, T. et al. J. Mol. Biol. 304, 397–410 (2000).
    Article CAS PubMed Google Scholar
  12. Ziegler, G.A., Vonrhein, C., Hanukoglu, I. & Schulz, G.E. J. Mol. Biol. 289, 981–990 (1999).
    Article CAS PubMed Google Scholar
  13. Kong, X.P., Onrust, R., O'Donnell, M. & Kuriyan, J. Cell 69, 425–437 (1992).
    Article CAS PubMed Google Scholar
  14. Luger, K., Mader, A.W., Richmond, R.K., Sargent, D.F. & Richmond, T.J. Nature 389, 251–260 (1997).
    Article CAS PubMed Google Scholar
  15. Uhlmann, F. Curr. Biol. 11, R384–387 (2001).
    Article CAS PubMed Google Scholar
  16. Demeret, C., Vassetzky, Y. & Mechali, M. Oncogene 20, 3086–3093 (2001).
    Article CAS PubMed Google Scholar
  17. Benbow, R.M. Science Prog. 76, 425–450 (1992).
    CAS Google Scholar
  18. Li, T.K. et al. Genes Dev. 13, 1553–1560 (1999).
    Article CAS PubMed PubMed Central Google Scholar
  19. Montague, J.W., Hughes, F.M. Jr & Cidlowski, J.A. J. Biol. Chem. 272, 6677–6684 (1997).
    Article CAS PubMed Google Scholar
  20. Otwinowski, Z. & Minor, W. Methods Enzymol. 276, 307–326 (1997).
    Article CAS PubMed Google Scholar
  21. Terwilliger, T.C. & Berendzen, J. Acta Crystallogr. D 55, 849–861 (1999).
    Article CAS PubMed PubMed Central Google Scholar
  22. Perrakis, A., Morris, R. & Lamzin, V.S. Nature Struct. Biol. 6, 458–463 (1999).
    Article CAS PubMed Google Scholar
  23. Brünger, A.T. et al. Acta Crystallogr. D 54, 905–921 (1998).
    Article PubMed Google Scholar
  24. Jones, T.A., Zou, J.-Y., Cowan, S.W. & Kjeldgaard, M. Acta Crystallogr. A 47, 110–119 (1991).
    Article PubMed Google Scholar
  25. Evans, S.V. J. Mol. Graph. 11, 134–138 (1993).
    Article CAS PubMed Google Scholar
  26. Nicholls, A., Sharp, K.A. & Honig, B. Proteins 11, 281–296 (1991).
    Article CAS PubMed Google Scholar
  27. Katchalski-Katzir, E. et al. Proc. Natl. Acad. Sci. USA 89, 2195–2199 (1992).
    Article CAS PubMed PubMed Central Google Scholar
  28. Loeffler, M. et al. FASEB J. 15, 758–767 (2001).
    Article CAS PubMed Google Scholar
  29. Daugas, E. et al. FASEB J. 14, 729–739 (2000).
    Article CAS PubMed Google Scholar
  30. Ravagnan, L. et al. Nature Cell Biol. 3, 839–843 (2001).
    Article CAS PubMed Google Scholar

Download references

Acknowledgements

We thank N. Lue and J. Wang for discussions; the laboratories of H. Robertson, J. Darnel, S. Chen-Kiang and W. Muller for technical help and staff at the advanced photon source for assistance with data collection. This work was partially supported by a special grant from the Ligue contre le Cancer and the European Commission. H.Y. is a Revson postdoctoral fellow and H.W. is a Pew scholar of biomedical sciences and a Rita Allen Scholar.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, 10021, New York, USA
    Hong Ye, Nicolas C. Stephanou, Sulin Jiang & Hao Wu
  2. Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, F-94805, France
    Celine Cande, Nathanael Larochette, Eric Daugas & Guido Kroemer
  3. INSERM U-517, Faculty of Medicine and Pharmacy, 7 Boulevard Jeanne d'Arc, Dijon, 21033, France
    Sundeep Gurbuxani & Carmen Garrido

Authors

  1. Hong Ye
  2. Celine Cande
  3. Nicolas C. Stephanou
  4. Sulin Jiang
  5. Sundeep Gurbuxani
  6. Nathanael Larochette
  7. Eric Daugas
  8. Carmen Garrido
  9. Guido Kroemer
  10. Hao Wu

Corresponding author

Correspondence toHao Wu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

About this article

Cite this article

Ye, H., Cande, C., Stephanou, N. et al. DNA binding is required for the apoptogenic action of apoptosis inducing factor.Nat Struct Mol Biol 9, 680–684 (2002). https://doi.org/10.1038/nsb836

Download citation

This article is cited by