Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesis.
Chromosomal translocations involving the human CBFB gene, which codes for the non-DNA binding subunit of CBF (CBF beta), are associated with a large percentage of human leukemias. The translocation inv(16) that disrupts the CBFB gene produces a chimeric protein composed of the heterodimerization domain of CBF beta fused to the C-terminal coiled-coil domain from smooth muscle myosin heavy chain (CBF beta-SMMHC). Isothermal titration calorimetry results show that this fusion protein binds the Runt domain from Runx1 (CBF alpha) with higher affinity than the native CBF beta protein. NMR studies identify interactions in the CBF beta portion of the molecule, as well as the SMMHC coiled-coil domain. This higher affinity provides an explanation for the dominant negative phenotype associated with a knock-in of the CBFB-MYH11 gene and also helps to provide a rationale for the leukemia-associated dysregulation of hematopoietic development that this protein causes.
Lukasik
Stephen M
SM
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908, USA.
Zhang
Lina
L
Corpora
Takeshi
T
Tomanicek
Sarah
S
Li
Yuanhong
Y
Kundu
Mondira
M
Hartman
Kari
K
Liu
P Paul
PP
Laue
Thomas M
TM
Biltonen
Rodney L
RL
Speck
Nancy A
NA
Bushweller
John H
JH
D000595:Amino Acid Sequence; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors / Q000378:metabolism*
C095514:CBFbeta-MYH11 fusion protein; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors