title: Molecular functions of the TLE tetramerization domain in Wnt target gene repression.
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.
authors.affiliation: Departments of Structural Biology and Molecular & Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jayanth V
authors.initials: JV
authors.lastname: Chodaparambil
authors.forename: Kira T
authors.initials: KT
authors.lastname: Pate
authors.forename: Margretta R D
authors.initials: MR
authors.lastname: Hepler
authors.forename: Becky P
authors.initials: BP
authors.lastname: Tsai
authors.forename: Uma M
authors.initials: UM
authors.lastname: Muthurajan
authors.forename: Karolin
authors.initials: K
authors.lastname: Luger
authors.forename: Marian L
authors.initials: ML
authors.lastname: Waterman
authors.forename: William I
authors.initials: WI
authors.lastname: Weis
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000378:metabolism*; D056970:Co-Repressor Proteins; D003461:Crystallography; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D008958:Models, Molecular; D008961:Models, Structural; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D056970:Co-Repressor Proteins; D006657:Histones; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C407909:TCF3 protein, human; C499043:TLE1 protein, human