Energetic and functional contribution of residues in the core binding factor beta (CBF beta) subunit to heterodimerization with CBF alpha

Core-binding factors (CBFs) are a small family of heterodimeric transcripti on factors that play critical roles in several developmental pathways, incl uding hematopoiesis and bone development. Mutations in CBF genes are found in leukemias and bone disorders. CBFs consist of a DNA-binding CBF alpha su bunit (Runx1, Runx2, or Runx3) and a non-DNA-binding CEF beta subunit. CBF alpha binds DNA in a sequence-specific manner, whereas CBF beta enhances DN A binding by CBF alpha. Recent structural analyses of the DNA-binding Runt domain of CBF alpha and the CBF beta subunit identified the heterodimerizat ion surfaces on each subunit. Here we identify amino acids in CBF beta that mediate binding to CBF alpha. We determine the energy contributed by each of these amino acids to heterodimerization and the importance of these resi dues for in vivo function. These data refine the structural analyses and fu rther support the hypothesis that CBF beta enhances DNA binding by inducing a conformational change in the Runt domain.