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.

Immunoglobulin motif DNA recognition and heterodimerization of the PEBP2/CBF Runt domain

Abstract

The polyomavirus enhancer binding protein 2 (PEBP2) or core binding factor (CBF) is a heterodimeric enhancer binding protein that is associated with genetic regulation of hematopoiesis and osteogenesis. Aberrant forms of PEBP2/CBF are implicated in the cause of the acute human leukemias and in a disorder of bone development known as cleidocranial dysplasia. The common denominator in the natural and mutant forms of this protein is a highly conserved domain of PEBP2/CBFα, termed the Runt domain (RD), which is responsible for both DNA binding and heterodimerization with the β subunit of PEBP2/CBF. The three-dimensional structure of the RD bound to DNA has been determined to be an S-type immunoglobulin fold, establishing a structural relationship between the RD and the core DNA binding domains of NF-κB, NFAT1, p53 and the STAT proteins. NMR spectroscopy of a 43.6 kD RD–β–DNA ternary complex identified the surface of the RD in contact with the β subunit, suggesting a mechanism for the enhancement of RD DNA binding by β. Analysis of leukemogenic mutants within the RD provides molecular insights into the role of this factor in leukemogenesis and cleidocranial dysplasia.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Three-dimensional structure of the Runt domain and its interaction with the β subunit.
Figure 2: Folding topology of Ig domain DNA binding proteins.
Figure 3: Identification of the heterodimerization surface for PEBP2/CBFβ.
Figure 4: Mapping of the β heterodimerization surface of the RD onto the three-dimensional structure.

Accession codes

Accessions

Protein Data Bank

References

  1. Crute, B. E., Lewis, A. F., Wu, Z., Bushweller, J. H. & Speck, N. A. J. Biol. Chem. 271, 26251– 26260 (1996).

    Article  CAS  Google Scholar 

  2. Cho, Y., Gorina, S., Jeffrey, P. D. & Pavletich, N. P. Science 265, 346–355 ( 1994).

    Article  CAS  Google Scholar 

  3. Ghosh, G., van Duyne, G., Ghosh, S. & Sigler, P. B. Nature 373, 303–310 (1995).

    Article  CAS  Google Scholar 

  4. Müller, C. W., Rey, F. A., Sodeoka, M., Verdine, G. L. & Harrison, S. C. Nature 373, 311– 317 (1995).

    Article  Google Scholar 

  5. Chen, L., Glover, J. N. M., Hogan, P. G., Rao, A. & Harrison, S. C. Nature 392, 42–48 (1998).

    Article  CAS  Google Scholar 

  6. Zhou, P., Sun, L.-J. Dötsch, V., Wagner, G. & Verdine, G. L. Cell 92, 687–696 (1998).

    Article  CAS  Google Scholar 

  7. Chen, X. et al. Cell 93, 827–839 (1998).

    Article  CAS  Google Scholar 

  8. Becker, S., Groner, B. & Müller C. W. Nature 394, 145– 151 (1998).

    Article  CAS  Google Scholar 

  9. Clore, G. M. & Gronenborn, A. M. Protein Sci. 3 , 372–390 (1994).

    Article  CAS  Google Scholar 

  10. Kamachi, Y. et al. J. Virol. 64, 4808– 4819 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kagoshima, H., Akamatsu, Y., Ito, Y. & Shigesada, K. J. Biol. Chem. 271, 33074–33082 ( 1996).

    Article  CAS  Google Scholar 

  12. Osato, M. et al. Blood 93, 1817–1824 (1999).

    CAS  PubMed  Google Scholar 

  13. Akamatsu, Y. et al. J. Biol. Chem. 272, 14497– 14500 (1997).

    Article  CAS  Google Scholar 

  14. Akamatsu, Y., Tsukumo, S., Kagoshima, H., Tsurushita, N. & Shigesada, K. Gene 185, 111–117 (1997).

    Article  CAS  Google Scholar 

  15. Lee, B. et al. Nature Genet. 16, 307–310 (1997).

    Article  CAS  Google Scholar 

  16. Lenny, N., Meyers, S. & Hiebert, S. W. Oncogene 11, 1761– 1769 (1995).

    CAS  PubMed  Google Scholar 

  17. Goger, M. et al. Nature Struct. Biol. 6, 620– 623 (1999).

    Article  CAS  Google Scholar 

  18. Ogawa, E. et al. Virol. 194, 314–331 (1993).

    Article  CAS  Google Scholar 

  19. Wang, S. et al. Mol. Cell. Biol.> 13, 3324– 3339. (1993).

    Article  CAS  Google Scholar 

  20. Kim, W-Y. et al. EMBO J. 18, 1609–1620 (1999).

    Article  CAS  Google Scholar 

  21. Look, A.T. Science 278, 1059–1064 ( 1997).

    Article  CAS  Google Scholar 

  22. Lu, J. et al. Mol. Cell. Biol. 15, 1651– 1661 (1995).

    Article  CAS  Google Scholar 

  23. Chiba, N. et al. Oncogene 14, 2543–2552 (1997).

    Article  CAS  Google Scholar 

  24. Kanno, Y., Kanno, T., Sakakura, C., Bae, S-C., & Ito Y. Mol. Cell. Biol. 18, 4252–4261 (1998).

    Article  CAS  Google Scholar 

  25. Adya, N., Stacy, T., Speck, N. A. & Liu, P. P. Mol. Cell. Biol. 18, 7432–7443 ( 1998).

    Article  CAS  Google Scholar 

  26. Liu, P. et al. Cold Spring Harbor Symp. Quant. Biol. 59, 547–553 (1994).

    Article  CAS  Google Scholar 

  27. Bax, A. & Grzesiek, S. Acc. Chem. Res. 26, 131–138 (1993).

    Article  CAS  Google Scholar 

  28. Omichinski, J. G., Pedone, P. V., Felsenfeld, G., Gronenborn, A. M. & Clore, G. M. Nature Struct. Biol. 4, 122–132 (1997).

    Article  CAS  Google Scholar 

  29. Nilges, M. Prot. Struct. Funct. Genet. 17, 295– 309 (1993).

    Article  Google Scholar 

  30. Brünger, A. T. X-PLOR Manual, Version 3.1 (Yale University Press, New Haven, Connecticut; 1992).

    Google Scholar 

  31. Garrett, D. S. et al. J. Magn Reson. (B) 104, 99– 103 (1994).

    Article  CAS  Google Scholar 

  32. Kuszewski, J., Gronenborn, A. M. & Clore, G. M. J. Magn. Reson. 125, 171– 177 (1997).

    Article  CAS  Google Scholar 

  33. Bork, P., Holm, L. & Sander, C. J. Mol. Biol. 242, 309– 320 (1994).

    CAS  PubMed  Google Scholar 

  34. Carson, M. J. Mol. Graphics 5, 103–106 (1987).

    Article  CAS  Google Scholar 

  35. Nicholls, A., Sharp, K. & Honig, B. Proteins 11, 281– 296. (1991).

    Article  CAS  Google Scholar 

  36. Laskowski, R. A., Rullmann, J. A., MacArthur, M. W., Kaptein, R. & Thornton, J. M. J. Biomol. NMR 8 , 477–486. (1996).

    Article  CAS  Google Scholar 

  37. Sippl, M. J. Proteins 17, 355–362. ( 1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge many stimulating discussions with L. Glaser, J. Hill, A. Kim, A. Seth and M. Osato. This work was supported in part by generous grants from the Sidney Kimmel Cancer Foundation, the Alexander and Alexandrine Sinsheimer Foundation and the New York Community Trust to M.H.W., a postdoctural fellowship to V.G. form the Leukemia Research Foundation and by grants from the Ministry of Education, Science, Culture and Sports of Japan to Y. I and K.S.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Milton H. Werner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagata, T., Gupta, V., Sorce, D. et al. Immunoglobulin motif DNA recognition and heterodimerization of the PEBP2/CBF Runt domain. Nat Struct Mol Biol 6, 615–619 (1999). https://doi.org/10.1038/10658

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/10658

This article is cited by

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