Molecular functions of the TLE tetramerization domain in Wnt target gene repression.

Wnt signaling activates target genes by promoting association of the co-activator β-catenin with TCF/LEF transcription factors. In the absence of β-catenin, target genes are silenced by TCF-mediated recruitment of TLE/Groucho proteins, but the molecular basis for TLE/TCF-dependent repression is unclear. We describe the unusual three-dimensional structure of the N-terminal Q ...
domain of TLE1 that mediates tetramerization and binds to TCFs. We find that differences in repression potential of TCF/LEFs correlates with their affinities for TLE-Q, rather than direct competition between β-catenin and TLE for TCFs as part of an activation-repression switch. Structure-based mutation of the TLE tetramer interface shows that dimers cannot mediate repression, even though they bind to TCFs with the same affinity as tetramers. Furthermore, the TLE Q tetramer, not the dimer, binds to chromatin, specifically to K20 methylated histone H4 tails, suggesting that the TCF/TLE tetramer complex promotes structural transitions of chromatin to mediate repression.
Mesh Terms:
Animals, Basic Helix-Loop-Helix Transcription Factors, COS Cells, Cell Line, Cercopithecus aethiops, Chromatin, Crystallography, Gene Expression Regulation, Histones, Humans, Methylation, Mice, Models, Molecular, Models, Structural, Mutation, Protein Binding, Protein Multimerization, Protein Structure, Tertiary, Repressor Proteins, Signal Transduction, TCF Transcription Factors, Transcriptional Activation, Wnt Proteins, beta Catenin
EMBO J.
Date: Apr. 01, 2014
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