期刊
EMBO JOURNAL
卷 33, 期 7, 页码 719-731出版社
WILEY
DOI: 10.1002/embj.201387188
关键词
chromatin; TLE/groucho; TCF/LEF; Wnt signaling
资金
- American Heart Association fellowship
- U.S. National Institutes of Health [GM56169]
- NIH [CA096878, CA108697, P30CA062203, P01-GM088409]
- Howard Hughes Medical Institute
Synopsis image 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. Abstract Wnt signaling activates target genes by promoting association of the co-activator beta-catenin with TCF/LEF transcription factors. In the absence of beta-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 beta-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.
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