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J. Biol. Chem., Vol. 278, Issue 35, 33097-33104, August 29, 2003

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Mutagenesis of the Runt Domain Defines Two Energetic Hot Spots for Heterodimerization with the Core Binding Factor Subunit^*

Lina Zhang , Zhe Li , Jiangli Yan , Padmanava Pradhan , Takeshi Corpora ¶, Matthew D. Cheney , Jerónimo Bravo || **, Alan J. Warren ||, John H. Bushweller  ¶  and Nancy A. Speck  

From the Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, the Department of Molecular Physiology and Biological Physics and the ^¶Department of Chemistry, University of Virginia, Charlottesville, Virginia 22906, and ^||MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom

Core-binding factors (CBFs) are a small family of heterodimeric transcription factors that play critical roles in several developmental pathways and in human disease. Mutations in CBF genes are found in leukemias, bone disorders, and gastric cancers. CBFs consist of a DNA-binding CBF subunit (Runx1, Runx2, or Runx3) and a non-DNA-binding CBF subunit. CBF binds DNA in a sequence-specific manner, whereas CBF enhances DNA binding by CBF. Both DNA binding and heterodimerization with CBF are mediated by a single domain in the CBF subunits known as the "Runt domain." We analyzed the energetic contribution of amino acids in the Runx1 Runt domain to heterodimerization with CBF. We identified two energetic "hot spots" that were also found in a similar analysis of CBF (Tang, Y.-Y., Shi, J., Zhang, L., Davis, A., Bravo, J., Warren, A. J., Speck, N. A., and Bushweller, J. H. (2000) J. Biol. Chem. 275, 39579–39588). The importance of the hot spot residues for Runx1 function was demonstrated in in vivo transient transfection assays. These data refine the structural analyses and further our understanding of the Runx1-CBF interface.

Received for publication, April 15, 2003 , and in revised form, June 12, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Present address: Structural Biology Program, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, E-28029 Madrid, Spain.

Supported by the United States Public Health Service Grant R01 AI39536 and the Leukemia and Lymphoma Society Grant 6158.

Supported by United States Public Health Service Grants R01 CA58343 and CA75611. To whom correspondence should be addressed. Tel.: 603-650-1159; Fax: 603-650-1128; E-mail: nancy.speck{at}dartmouth.edu.

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