ECB-ART-40264BMC Genomics 2007 Jun 28;8:201. doi: 10.1186/1471-2164-8-201.
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Prevalence of the EH1 Groucho interaction motif in the metazoan Fox family of transcriptional regulators.
BACKGROUND: 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. 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. RESULTS: Systematic 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 alpha-helices, and wheel modeling revealed an amphipathicity that supports this secondary structure prediction. CONCLUSION: A 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.
PubMed ID: 17598915
PMC ID: PMC1939712
Article link: BMC Genomics
Species referenced: Echinodermata
Genes referenced: en1 ephx2 foxc1 foxd4 foxg1 foxq1 irak1bp1 LOC100887844 LOC100890537 LOC115925415 LOC591473 polr3a tle2
Article Images: [+] show captions
|Figure 1. A phylogenetic tree for proteins of the FoxE subclass and the FoxC and FoxD outgroups. A neighbor-joining method was used to construct the tree topology and bootstrapping values are shown at each branch point (percentage of 1000 bootstrap samples) using the MEGA 3.1 software. Gaps were deleted in pairwise comparisons. The distance scale below the tree represents the number of substitutions per site. The C and D families are collapsed for better illustration. Protein sequences that lack a recognizable eh1-like motif are represented by blue triangles. Proteins and subclasses that contain an eh1-like motif are represented by red circles.|
|Figure 2. The diagrams summarize the amino acid compositions of the eh1-like motifs identified in Fox proteins. The amino acid usage frequency of eh1-like motifs identified in invertebrate (A) and vertebrate (B) Fox proteins. The diagrams were generated with the WebLogo program .|
|Figure 3. (A) Multiple sequence alignments of the α-helical region of an ultraspiracle ligand binding domain from Drosophila (ULBD), α-helix of a conserved hypothetical protein from C. tepidum (CHPfCT), and the eh1 motifs of human FoxB1, murine FoxB2 and amphioxus FoxE4 proteins, which have a high likelihood of α-helix formation. (B) Sequence alignment for the α-helical region of the Hepatitis C Virus RNA Polymerase Genotype 2a (HCVRPG) and the eh1 motif of the cnidarian Fox1 protein. The defined α-helices are represented as red solid boxes and predicted α-helices are shown as red dotted boxes. Amino acid similarities are shown in yellow. hum, Human; mus, Mouse; amp, amphioxus; nem, Sea Anemone. Wheel models of the eh1-like motifs of Xenopus FoxB1 (C) and amphioxus FoxE4 (D) form an amphipathic α-helical structure. Hydrophobic residues on the wheel are shown in the red, hydrophilic residues are shown in the blue, and non-charged residues are shown in the gray.|
|Figure 4. The positional distribution of the C-terminal eh1-like motifs in Fox proteins of the B, E, H and Q subclasses (A) and the A D, C and I subclasses (B). Size of polylinker represents the distance between the first residue of the eh1 motif and the conserved C-terminal residue of the winged helix DNA-binding domain.|
|Figure 5. Positional fluctuations of eh1-like motifs in the ortholog and paralog groups of vertebrate Fox proteins. (A) Positional fluctuations of the eh1-like motifs of the ortholog and paralog groups of the A, C and D subclasses. (B) Positional fluctuations of the eh1-like motifs of the ortholog and paralog groups of the B, E, H and Q subclasses. Polylinker represents the distance between the first residue of the eh1-like motif and the conserved C-terminal residue of the winged helix DNA-binding domain. The paralog groups within a Fox subclass are indicated on the x-axis.|
References [+] :
Andrioli, Groucho-dependent repression by sloppy-paired 1 differentially positions anterior pair-rule stripes in the Drosophila embryo. 2005, Pubmed