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
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Crute, B. E., Lewis, A. F., Wu, Z., Bushweller, J. H. & Speck, N. A. J. Biol. Chem. 271, 26251– 26260 (1996).
Cho, Y., Gorina, S., Jeffrey, P. D. & Pavletich, N. P. Science 265, 346–355 ( 1994).
Ghosh, G., van Duyne, G., Ghosh, S. & Sigler, P. B. Nature 373, 303–310 (1995).
Müller, C. W., Rey, F. A., Sodeoka, M., Verdine, G. L. & Harrison, S. C. Nature 373, 311– 317 (1995).
Chen, L., Glover, J. N. M., Hogan, P. G., Rao, A. & Harrison, S. C. Nature 392, 42–48 (1998).
Zhou, P., Sun, L.-J. Dötsch, V., Wagner, G. & Verdine, G. L. Cell 92, 687–696 (1998).
Chen, X. et al. Cell 93, 827–839 (1998).
Becker, S., Groner, B. & Müller C. W. Nature 394, 145– 151 (1998).
Clore, G. M. & Gronenborn, A. M. Protein Sci. 3 , 372–390 (1994).
Kamachi, Y. et al. J. Virol. 64, 4808– 4819 (1990).
Kagoshima, H., Akamatsu, Y., Ito, Y. & Shigesada, K. J. Biol. Chem. 271, 33074–33082 ( 1996).
Osato, M. et al. Blood 93, 1817–1824 (1999).
Akamatsu, Y. et al. J. Biol. Chem. 272, 14497– 14500 (1997).
Akamatsu, Y., Tsukumo, S., Kagoshima, H., Tsurushita, N. & Shigesada, K. Gene 185, 111–117 (1997).
Lee, B. et al. Nature Genet. 16, 307–310 (1997).
Lenny, N., Meyers, S. & Hiebert, S. W. Oncogene 11, 1761– 1769 (1995).
Goger, M. et al. Nature Struct. Biol. 6, 620– 623 (1999).
Ogawa, E. et al. Virol. 194, 314–331 (1993).
Wang, S. et al. Mol. Cell. Biol.> 13, 3324– 3339. (1993).
Kim, W-Y. et al. EMBO J. 18, 1609–1620 (1999).
Look, A.T. Science 278, 1059–1064 ( 1997).
Lu, J. et al. Mol. Cell. Biol. 15, 1651– 1661 (1995).
Chiba, N. et al. Oncogene 14, 2543–2552 (1997).
Kanno, Y., Kanno, T., Sakakura, C., Bae, S-C., & Ito Y. Mol. Cell. Biol. 18, 4252–4261 (1998).
Adya, N., Stacy, T., Speck, N. A. & Liu, P. P. Mol. Cell. Biol. 18, 7432–7443 ( 1998).
Liu, P. et al. Cold Spring Harbor Symp. Quant. Biol. 59, 547–553 (1994).
Bax, A. & Grzesiek, S. Acc. Chem. Res. 26, 131–138 (1993).
Omichinski, J. G., Pedone, P. V., Felsenfeld, G., Gronenborn, A. M. & Clore, G. M. Nature Struct. Biol. 4, 122–132 (1997).
Nilges, M. Prot. Struct. Funct. Genet. 17, 295– 309 (1993).
Brünger, A. T. X-PLOR Manual, Version 3.1 (Yale University Press, New Haven, Connecticut; 1992).
Garrett, D. S. et al. J. Magn Reson. (B) 104, 99– 103 (1994).
Kuszewski, J., Gronenborn, A. M. & Clore, G. M. J. Magn. Reson. 125, 171– 177 (1997).
Bork, P., Holm, L. & Sander, C. J. Mol. Biol. 242, 309– 320 (1994).
Carson, M. J. Mol. Graphics 5, 103–106 (1987).
Nicholls, A., Sharp, K. & Honig, B. Proteins 11, 281– 296. (1991).
Laskowski, R. A., Rullmann, J. A., MacArthur, M. W., Kaptein, R. & Thornton, J. M. J. Biomol. NMR 8 , 477–486. (1996).
Sippl, M. J. Proteins 17, 355–362. ( 1993).
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
Corresponding author
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/10658
This article is cited by
-
RUN(X) out of blood: emerging RUNX1 functions beyond hematopoiesis and links to Down syndrome
Human Genomics (2023)
-
Clonal hematopoiesis of indeterminate potential in the companion dog
Leukemia (2022)
-
Transcriptional dysregulation during myeloid transformation in AML
Oncogene (2007)
-
Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles
The EMBO Journal (2007)
-
Oncogenic potential of the RUNX gene family: ‘Overview’
Oncogene (2004)