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

EMBO J. 2014 Apr 1;33(7):719-31. doi: 10.1002/embj.201387188. Epub 2014 Mar 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Chromatin / metabolism*
  • Co-Repressor Proteins
  • Crystallography
  • Gene Expression Regulation*
  • Histones / metabolism
  • Humans
  • Methylation
  • Mice
  • Models, Molecular*
  • Models, Structural
  • Mutation
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Repressor Proteins / chemistry
  • Repressor Proteins / metabolism*
  • Signal Transduction*
  • TCF Transcription Factors / metabolism
  • Transcriptional Activation
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • Co-Repressor Proteins
  • Histones
  • Repressor Proteins
  • TCF Transcription Factors
  • TCF3 protein, human
  • TLE1 protein, human
  • Wnt Proteins
  • beta Catenin