Energetic contribution of residues in the Runx1 Runt domain to DNA binding
Energetic contribution of residues in the Runx1 Runt domain to DNA binding
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DOI：
10.1074/jbc.m303973200
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发表时间：
2003-08-29
影响因子：
4.8
通讯作者：
Speck, NA
中科院分区：
文献类型：
--
作者：
Li, Z;Yan, JL;Speck, NA
核心结合因子（CBF）是一个小家族的异源二聚体转录因子，在造血和骨，胃上皮和本体感受神经元的发育中发挥关键作用。CBF基因突变见于白血病、骨疾病和胃癌。CBF由DNA结合CBF α亚基和非DNA结合CBF β亚基组成。DNA与CBF β的结合和异源二聚化由CBF α中的Runt结构域介导。在这里，我们报告了一个丙氨酸扫描诱变研究的Runt结构域的结构研究确定的目标氨基酸驻留在DNA或CBFbeta接口，以及在人类疾病中突变的氨基酸。我们确定了能量贡献的每个DNA接触残基在Runt域DNA结合的存在和不存在的CBFbeta。我们提出的机制，在造血和骨骼疾病中发现的Runt结构域的突变影响其对DNA的亲和力。
Core-binding factors (CBFs) are a small family of heterodimeric transcription factors that play critical roles in hematopoiesis and in the development of bone, stomach epithelium, and proprioceptive neurons. Mutations in CBF genes are found in leukemias, bone disorders, and gastric cancer. CBFs consist of a DNA-binding CBFalpha subunit and a non-DNA-binding CBFbeta subunit. DNA binding and heterodimerization with CBFbeta are mediated by the Runt domain in CBFalpha. Here we report an alanine-scanning mutagenesis study of the Runt domain that targeted amino acids identified by structural studies to reside at the DNA or CBFbeta interface, as well as amino acids mutated in human disease. We determined the energy contributed by each of the DNA-contacting residues in the Runt domain to DNA binding both in the absence and presence of CBFbeta. We propose mechanisms by which mutations in the Runt domain found in hematopoietic and bone disorders affect its affinity for DNA.