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 uncl...

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Published in:	The EMBO journal Vol. 33; no. 7; pp. 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:	Journal Article
Language:	English
Published:	London Blackwell Publishing Ltd 01-04-2014 Nature Publishing Group UK
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 TLE/groucho Wnt signaling TCF/LEF chromatin
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Summary:	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.
Bibliography:	American Heart Association U.S. Department of Energy U.S. National Institutes of Health - No. GM56169 NIH - No. CA096878; No. CA108697; No. P30CA062203; No. P01-GM088409 Howard Hughes Medical Institute Supplementary Figure 1Supplementary Figure 2Supplementary Figure 3Supplementary Figure 4Supplementary Figure 5Supplementary Table 1Supplementary Materials and MethodsReview Process File istex:A797D734C64F17DC6ED8C278C5082FEE551D2375 ark:/67375/WNG-2947CQ08-P ArticleID:EMBJ201387188 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Subject Categories Signal Transduction; Structural Biology
ISSN:	0261-4189 1460-2075
DOI:	10.1002/embj.201387188