Abstract
BackgroundThe Fox gene family comprises a large and functionally diverse group of forkhead-related transcriptional regulators, many of which are essential for metazoan embryogenesis and physiology. Defining conserved functional domains that mediate the transcriptional activity of Fox proteins will contribute to a comprehensive understanding of the biological function of Fox family genes.ResultsSystematic analysis of 458 protein sequences of the metazoan Fox family was performed to identify the presence of the engrailed homology-1 motif (eh1), a motif known to mediate physical interaction with transcriptional corepressors of the TLE/Groucho family. Greater than 50% of Fox proteins contain sequences with high similarity to the eh1 motif, including ten of the nineteen Fox subclasses (A, B, C, D, E, G, H, I, L, and Q) and Fox proteins of early divergent species such as marine sponge. The eh1 motif is not detected in Fox proteins of the F, J, K, M, N, O, P, R and S subclasses, or in yeast Fox proteins. The eh1-like motifs are positioned C-terminal to the winged helix DNA-binding domain in all subclasses except for FoxG proteins, which have an N-terminal motif. Two similar eh1-like motifs are found in the zebrafish FoxQ1 and in FoxG proteins of sea urchin and amphioxus. The identification of eh1-like motifs by manual sequence alignment was validated by statistical analyses of the Swiss protein database, confirming a high frequency of occurrence of eh1-like sequences in Fox family proteins. Structural predictions suggest that the majority of identified eh1-like motifs are short α-helices, and wheel modeling revealed an amphipathicity that supports this secondary structure prediction.ConclusionA search for eh1 Groucho interaction motifs in the Fox gene family has identified eh1-like sequences in greater than 50% of Fox proteins. The results predict a physical and functional interaction of TLE/Groucho corepressors with many members of the Fox family of transcriptional regulators. Given the functional importance of the eh1 motif in transcriptional regulation, our annotation of this motif in the Fox gene family will facilitate further study of the diverse transcriptional and regulatory roles of Fox family proteins.
Highlights
The Fox gene family comprises a large and functionally diverse group of forkhead-related transcriptional regulators, many of which are essential for metazoan embryogenesis and physiology
A phylogenetic tree for the Fox gene family was constructed in which the presence of an eh1-like motif within individual Fox proteins is indicated [see Additional files 1 and 2]
We have identified the presence of eh1-like Groucho interaction motifs in ten subclasses of the Fox family of transcriptional regulators by systematically analyzing 458 protein sequences of nineteen Fox subclasses
Summary
The Fox gene family comprises a large and functionally diverse group of forkhead-related transcriptional regulators, many of which are essential for metazoan embryogenesis and physiology. In the case of transcriptional repressors, such short protein regions can autonomously mediate repression when fused to a heterologous DNA-binding domain [1,2] It appears that these conserved regions form either α-helices or binding pockets to provide specific interacting surfaces for transcriptional corepressors. We focus on identifying and analyzing the Engrailed homology region-1 (eh1) transcriptional repression motif in the Fox gene family of forkhead-related transcriptional regulators. This motif is known to mediate specific physical interactions of a number of protein families with transcriptional corepressors of the TLE/Groucho protein family [4,5,6,7]
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