Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta.
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.
Kanagawa Academy of Science and Technology (KAST), Yokohama City University School of Medicine, 3-9 Fukuura, Yokohama 236-0004, Kanazawa-ku, Japan. tahir@med.yokohama-cu.ac.jp
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Tahirov
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Inoue-Bungo
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Morii
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Fujikawa
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Sasaki
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Kimura
M
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Shiina
K
K
Sato
T
T
Kumasaka
M
M
Yamamoto
S
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Ishii
K
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Ogata
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D002151:Calorimetry; D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D007938:Leukemia / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493726:Runx1 protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C406688:core binding factor alpha; D004247:DNA