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

• Published in: The EMBO journal 2014-04, Vol.33 (7), p.719-731
• Main Authors: Chodaparambil, Jayanth V, Pate, Kira T, Hepler, Margretta R D, Tsai, Becky P, Muthurajan, Uma M, Luger, Karolin, Waterman, Marian L, Weis, William I
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; beta Catenin - metabolism; Cell Line; Chlorocebus aethiops; Chromatin; Chromatin - metabolism; Competition; COS Cells; Crystallography; EMBO37; EMBO40; Gene expression; Gene Expression Regulation; Histones - metabolism; Humans; Methylation; Mice; Models, Molecular; Models, Structural; Molecular biology; Mutation; Protein Binding; Protein Multimerization; Protein Structure, Tertiary; Repressor Proteins - chemistry; Repressor Proteins - metabolism; Signal Transduction; TCF Transcription Factors - metabolism; TCF/LEF; TLE/groucho; Transcription factors; Transcriptional Activation; Wnt Proteins - metabolism; Wnt signaling
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1002/embj.201387188

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. Synopsis Bill Weis and colleagues present an unusual tetramer fold for the N‐terminal domain of the Groucho/TLE1 repressor. Their functional results propose chromatin binding, rather than competition for TCF as mechanism for Wnt‐target gene repression. The N‐terminal tetramerization domain of the transcriptional co‐repressor TLE1 forms an extended, interdigitated dimer of dimers TLE1 binds the repressive TCF3 and TCF4 proteins more strongly than the activating TCF1 and LEF1 proteins There is no direct competition between TLE and ß‐catenin for TCF/LEF binding, suggesting that other factors mediate the switch between repression and activation of Wnt target genes The TLE N‐terminal domain can bind chromatin through its interaction with K20 methylated H4 tails. Graphical Abstract Bill Weis and colleagues present an unusual tetramer fold for the N‐terminal domain of the Groucho/TLE1 repressor. Their functional results propose chromatin binding, rather than competition for TCF as mechanism for Wnt‐target gene repression.