AML1/Runx-1 Runt结构域对DNA识别的结构分析及其受CBFβ的变构调控

Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta.

作者信息

Tahirov T H, Inoue-Bungo T, Morii H, Fujikawa A, Sasaki M, Kimura K, Shiina M, Sato K, Kumasaka T, Yamamoto M, Ishii S, Ogata K

机构信息

Kanagawa Academy of Science and Technology (KAST), Yokohama City University School of Medicine, 3-9 Fukuura, Yokohama 236-0004, Kanazawa-ku, Japan.

出版信息

Cell. 2001 Mar 9;104(5):755-67. doi: 10.1016/s0092-8674(01)00271-9.

DOI:10.1016/s0092-8674(01)00271-9

PMID:11257229

Abstract

The core binding factor (CBF) heterodimeric transcription factors comprised of AML/CBFA/PEBP2alpha/Runx and CBFbeta/PEBP2beta 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/CBFalpha(Runt domain)-CBFbeta(core domain)-C/EBPbeta(bZip)-DNA, AML1/Runx-1/CBFalpha(Runt domain)-C/EBPbeta(bZip)-DNA, and AML1/Runx-1/CBFalpha(Runt domain)-DNA complexes. The hydrogen bonding network formed among CBFalpha(Runt domain) and CBFbeta, and CBFalpha(Runt domain) and DNA revealed the allosteric regulation mechanism of CBFalpha(Runt domain)-DNA binding by CBFbeta. The point mutations of CBFalpha related to the aforementioned diseases were also mapped and their effect on DNA binding is discussed.

摘要

核心结合因子（CBF）异二聚体转录因子由AML/CBFA/PEBP2alpha/Runx和CBFbeta/PEBP2beta亚基组成，对造血细胞和骨细胞的分化至关重要，其突变与急性白血病和锁骨颅骨发育不全的发生密切相关。在此，我们展示了AML1/Runx-1/CBFalpha（Runt结构域）-CBFbeta（核心结构域）-C/EBPbeta（bZip）-DNA、AML1/Runx-1/CBFalpha（Runt结构域）-C/EBPbeta（bZip）-DNA以及AML1/Runx-1/CBFalpha（Runt结构域）-DNA复合物的晶体结构。CBFalpha（Runt结构域）与CBFbeta以及CBFalpha（Runt结构域）与DNA之间形成的氢键网络揭示了CBFbeta对CBFalpha（Runt结构域）-DNA结合的变构调节机制。还对与上述疾病相关的CBFalpha点突变进行了定位，并讨论了它们对DNA结合的影响。