Immunoglobulin motif DNA recognition and heterodimerization of the PEBP2/CBF Runt domain

The polyomavirus enhancer binding protein 2 (PEBP2) or core binding factor (CBF) is a heterodimeric enhancer binding protein that is associated with g enetic regulation of hematopoiesis and osteogenesis. Aberrant forms of PEBP 2/CBF are implicated in the cause of the acute human leukemias and in a dis order of bone development known as cleidocranial dysplasia. The common deno minator in the natural and mutant forms of this protein is a highly conserv ed domain of PEBP2/CBF alpha, termed the Runt domain (RD), which is respons ible for both DNA binding and heterodimerization with the beta subunit of P EBP2/CBF. The three-dimensional structure of the RD bound to DNA has been d etermined to be an S-type immunoglobulin fold, establishing a structural re lationship between the RD and the core DNA binding domains of NF-kappa B, N FAT1, p53 and the STAT proteins, NMR spectroscopy of a 43.6 kD RD-beta-DNA ternary complex identified the surface of the RD in contact with the beta s ubunit, suggesting a mechanism for the enhancement of RD DNA binding by bet a. Analysis of leukemogenic mutants within the RD provides molecular insigh ts into the role of this factor in leukemogenesis and cleidocranial dysplas ia.