BoneKEy-Osteovision | Commentary
Structure function of Cbfa proteins
DOI:10.1138/2001023
The drosophila runt gene was the first member isolated from a family of transcription factors that have grown in number and importance over time (). Indeed, runt homologues have been identified in C. elegans, chick, mouse and humans, to cite a few species. They are characterized by a common DNA binding domain 128 amino acid long called the runt domain (). The growth of this family of proteins has been somewhat tumultuous as the three mammalian homologues of the drosophila runt gene have changed names over the past ten years. For the sake of simplicity they will be called Cbfa1, Cbfa2 (also known as AML1), and Cbfa3. In vertebrates the importance of these proteins stems from their involvement in critical cell differentiation processes such as hemotopoiesis (Cbfa2) and osteogenesis (cbfa1) (). Consistent with these functions, mutations in Cbfa1 and Cbfa2 cause cleidocranial dysplasia and familial platelet disorder respectively. Cbfa2 heterodimerizes with another protein termed CBFβ. This interaction occurs via the DNA binding (DBD) domain or runt domain of Cbfa2 (). The runt domain is nearly identical between the three Cbfa proteins and therefore these different functions arise from different patterns of expression and possibly from the presence of different domains in these proteins. For instance, an interaction Cbfa1/Cbfβ can only occur between a deletion mutant of Cbfa1 removing a domain rich in glutamine and alanine that is critical for transactivation and that is specific of Cbfa1 (). Although several crystal structures have been published for the Cbfa proteins and for Cbfβ () no structure of the heterodimeric complex has been shown yet.
In a paper recently published Tahirov et al.,() tried to tackle the structure of this heterodimer by analyzing this complex formed between the runt domain only of Cbfa2 or Cbfa1 and a truncated form of Cbfβ. What they showed is that the runt domain interacts with both the major and minor grooves of DNA and that Cbfb interacts with the runt domain at a site distant from the protein-DNA interface. Whether this may explain why Cbfβ does not interact with the full length Cbfa1 is a possibility. This study also provides a structural basis for the critical role of several residues in the runt domain whose mutations affect DNA binding and cause CCD. The Cbfa proteins are large proteins, and this makes obtaining a crystal structure of the entire molecule extremely difficult. Thus, in absence of such a crystal this study is particularly important for Cbfa2 and possibly Cbfa3, but given its structural characteristics, probably less informative to understand Cbfa1 biology.
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