Tang Y Y, Shi J, Zhang L, Davis A, Bravo J, Warren A J, Speck N A, Bushweller J H
Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
J Biol Chem. 2000 Dec 15;275(50):39579-88. doi: 10.1074/jbc.M007350200.
Core-binding factors (CBFs) are a small family of heterodimeric transcription factors that play critical roles in several developmental pathways, including hematopoiesis and bone development. Mutations in CBF genes are found in leukemias and bone disorders. CBFs consist of a DNA-binding CBFalpha subunit (Runx1, Runx2, or Runx3) and a non-DNA-binding CBFbeta subunit. CBFalpha binds DNA in a sequence-specific manner, whereas CBFbeta enhances DNA binding by CBFalpha. Recent structural analyses of the DNA-binding Runt domain of CBFalpha and the CBFbeta subunit identified the heterodimerization surfaces on each subunit. Here we identify amino acids in CBFbeta that mediate binding to CBFalpha. We determine the energy contributed by each of these amino acids to heterodimerization and the importance of these residues for in vivo function. These data refine the structural analyses and further support the hypothesis that CBFbeta enhances DNA binding by inducing a conformational change in the Runt domain.
核心结合因子（CBFs）是一个由异二聚体转录因子组成的小家族，在包括造血和骨骼发育在内的多种发育途径中发挥关键作用。CBF基因的突变见于白血病和骨骼疾病。CBFs由一个DNA结合性CBFα亚基（Runx1、Runx2或Runx3）和一个非DNA结合性CBFβ亚基组成。CBFα以序列特异性方式结合DNA，而CBFβ增强CBFα与DNA的结合。最近对CBFα的DNA结合Runt结构域和CBFβ亚基的结构分析确定了每个亚基上的异二聚化表面。在此，我们鉴定了CBFβ中介导与CBFα结合的氨基酸。我们确定了这些氨基酸中每一个对异二聚化的能量贡献以及这些残基对体内功能的重要性。这些数据完善了结构分析，并进一步支持了CBFβ通过诱导Runt结构域的构象变化来增强DNA结合的假说。
