The Ig fold of the core binding factor alpha Runt domain is a member of a family of structurally and functionally related Ig-fold DNA-binding domains

Background: CBFA is the DNA-binding subunit of the transcription factor com plex called core binding factor, or CBF. Knockout of the Cbfa2 gene in mice leads to embryonic lethality and a profound block in hematopoietic develop ment. Chromosomal disruptions of the human CBFA gene are associated with a large percentage of human leukemias. Results: Utilizing nuclear magnetic resonance spectroscopy we have determin ed the three-dimensional fold of the CBFA Runt domain in its DNA-bound stat e, showing that it is an s-type immunoglobulin (Ig) fold. DNA binding by th e Runt domain is shown to be mediated by loop regions located at both ends of the Runt domain Ig fold. A putative site for CBFB binding has been ident ified; the spatial location of this site provides a rationale for the abili ty of CBFB to modulate the affinity of the Runt domain for DNA. Conclusions: Structural comparisons demonstrate that the s-type Ig fold fou nd in the Runt domain is conserved in the Ig folds found in the DNA-binding domains of NF-kappa B, NFAT, p53, STAT-1, and the T-domain. Thus, these pr oteins form a family of structurally and functionally related DNA-binding d omains. Unlike the other members of this family, the Runt domain utilizes l oops at both ends of the Ig fold for DNA recognition.