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Letter
Nature Structural Biology  6, 620 - 623 (1999)
doi:10.1038/10664

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

Michael Goger1, 2, Vineet Gupta1, 2, Woo-Young Kim3, Katsuya Shigesada3, Yoshiaki Ito3 & Milton H. Werner2

1  These authors contributed equally to this work.

2  Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, Box 42, New York, NY 10021, USA.

3  Institute for Virus Research, Kyoto University, Japan.

Correspondence should be addressed to Milton H. Werner mwerner@portugal.rockfeller.edu
PEBP2/CBF is a heterodimeric transcription factor essential for genetic regulation of hematopoiesis and osteogenesis. DNA binding by PEBP2/CBFalpha 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 beta 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/CBFbeta to a portion of the smooth muscle myosin heavy chain (PEBP2/CBFbeta-SMMHC) that is causally associated with the onset of acute myeloid leukemia in humans. The three-dimensional structure of PEBP2/CBFbeta has been determined in solution and is shown to adopt a fold related to the beta-barrel oligomer binding motif. Direct analysis of a 43.6kD ternary RD−beta−DNA complex identifies the likely surface of beta in contact with the RD. The structure of PEBP2/CBFbeta enables a molecular understanding of the capacity of PEBP2/CBFbeta-SMMHC to sequester PEBP2/CBFalpha in the cytoplasm and therefore provides a molecular basis for understanding leukemogenic transformation.

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Nature Structural & Molecular Biology
ISSN: 1545-9993
EISSN: 1545-9985
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