Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4)

AFX is a human forkhead transcription factor. Based on results from studies of the orthologous transcription factor DAF-16 in Caenorhabditis elegans, it was suggested that some of the metabolic defects in both type I and type II diabetes may be due to unregulated activity of AFX. In the present stud y, we report the high-resolution NMR solution structure of the DNA binding domain of AFX. It is the first structure of the DNA binding domain from a s mall subfamily of forkhead transcription factors (i.e., AFX, FKHR, FKHRL1, FKHRL1P1, and FKHRP1). Despite rather low sequence identity for a protein w ithin the forkhead family, the structure is remarkably similar to those of the DNA binding domains of HNF3-gamma and FREAC-11, and to a lesser extent the DNA binding domain of Genesis which displays a slightly altered orienta tion of the DNA recognition helix. The high degree of structural similarity between the DNA binding domains of different forkhead transcription factor s implies that the repositioning of helix 3, observed for Genesis, cannot b e a general feature for modulation of the DNA binding specificity. Other me chanisms that could influence the DNA binding specificity are discussed.