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

PEBP2/CBF is a heterodimeric transcription factor essential for genetic reg ulation of hematopoiesis and osteogenesis. DNA binding by PEBP2/CBF alpha i s accomplished by a highly conserved DNA binding domain, the punt domain (R D), whose structure adopts an S-type immunoglobulin fold when bound to DNA, The supplementary subunit beta enhances DNA binding by the RD in vitro, bu t its role in the control of gene expression has remained largely unknown i n vivo. Chromosome 16 inversion creates a chimeric gene product fusing PEBP 2/CBF beta to a portion of the smooth muscle myosin heavy chain (PEBP2/CBF beta-SMMHC) that is causally associated with the onset of acute myeloid leu kemia in humans. The three-dimensional structure of PEBP2/CBF beta has been determined in solution and is shown to adopt a fold related to the beta-ba rrel oligomer binding motif, Direct analysis of a 43.6 kD ternary RD-beta-D NA complex identifies the likely surface of beta in contact with the RD. Th e structure of PEBP2/CBF beta enables a molecular understanding of the capa city of PEBP2/CBF beta-SMMHC to sequester PEBP2/CBF alpha in the cytoplasm and therefore provides a molecular basis for understanding leukemogenic tra nsformation.