Structural Analyses of DNA Recognition by the AML1/Runx-1 Runt Domain and Its Allosteric Control by CBFβ

Abstract

The core binding factor (CBF) heterodimeric transcription factors comprised of AML/CBFA/PEBP2α/Runx and CBFβ/PEBP2β subunits are essential for differentiation of hematopoietic and bone cells, and their mutation is intimately related to the development of acute leukemias and cleidocranial dysplasia. Here, we present the crystal structures of the AML1/Runx-1/CBFα(Runt domain)-CBFβ(core domain)-C/EBPβ(bZip)-DNA, AML1/Runx-1/CBFα(Runt domain)-C/EBPβ(bZip)-DNA, and AML1/Runx-1/CBFα(Runt domain)-DNA complexes. The hydrogen bonding network formed among CBFα(Runt domain) and CBFβ, and CBFα(Runt domain) and DNA revealed the allosteric regulation mechanism of CBFα(Runt domain)-DNA binding by CBFβ. The point mutations of CBFα related to the aforementioned diseases were also mapped and their effect on DNA binding is discussed.