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Molecular insights into PEBP2/CBFβ-SMMHC associated acute leukemia revealed from the structure of PEBP2/CBFβ

Abstract

PEBP2/CBF is a heterodimeric transcription factor essential for genetic regulation of hematopoiesis and osteogenesis. DNA binding by PEBP2/CBFα is accomplished by a highly conserved DNA binding domain, the Runt domain (RD), whose structure adopts an S-type immunoglobulin fold when bound to DNA. The supplementary subunit β enhances DNA binding by the RD in vitro , but its role in the control of gene expression has remained largely unknown in vivo. Chromosome 16 inversion creates a chimeric gene product fusing PEBP2/CBFβ to a portion of the smooth muscle myosin heavy chain (PEBP2/CBFβ-SMMHC) that is causally associated with the onset of acute myeloid leukemia in humans. The three-dimensional structure of PEBP2/CBFβ has been determined in solution and is shown to adopt a fold related to the β-barrel oligomer binding motif. Direct analysis of a 43.6kD ternary RD–β–DNA complex identifies the likely surface of β in contact with the RD. The structure of PEBP2/CBFβ enables a molecular understanding of the capacity of PEBP2/CBFβ-SMMHC to sequester PEBP2/CBFα in the cytoplasm and therefore provides a molecular basis for understanding leukemogenic transformation.

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Figure 1: Three-dimensional structure of PEBP2/CBFβ.
Figure 2: Chemical shift perturbation mapping of the PEBP2/CBFβ interaction surface for the PEBP2/CBFα Runt domain.
Figure 3: Binding surface of PEBP2/CBFβ for the Runt domain.
Figure 4: Arginine cluster of PEBP2/CBFβ.

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Acknowledgements

The authors wish to acknowledge many stimulating discussions with T. Nagata, L. Glaser, J. Hill, A. Kim, D. Sorce, A. Seth and M. Osato. This work was supported in part by generous grants from the Sidney Kimmel Cancer Foundation, the Alexander and Alexandrine Sinsheimer Foundation and the New York Community Trust to M.H.W., a postdoctoral fellowship from the Leukemia Research Foundation to V.G. and grants from the Ministry of Education, Science, Culture and Sports of Japan to Y.I. and K.S.

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Correspondence to Milton H. Werner.

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Goger, M., Gupta, V., Kim, WY. et al. Molecular insights into PEBP2/CBFβ-SMMHC associated acute leukemia revealed from the structure of PEBP2/CBFβ. Nat Struct Mol Biol 6, 620–623 (1999). https://doi.org/10.1038/10664

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