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β-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation

Nature Structural & Molecular Biology volume 12, pages 364–371 (2005)Cite this article

Abstract

Wnt growth factors mediate cell fate determination during embryogenesis and in the renewal of tissues in the adult. Wnts act by stabilizing cellular levels of the transcriptional coactivator β-catenin, which forms complexes with sequence-specific DNA-binding Tcf/Lef transcription factors. In the absence of nuclear β-catenin, Tcf/Lefs act as transcriptional repressors by binding to Groucho/TLE proteins. The molecular basis of the switch from transcriptional repression to activation during Wnt signaling has not been clear, in particular whether factors other than β-catenin are required to disrupt the interaction between Groucho/TLE and Tcf/Lef. Using highly purified proteins, we demonstrate that β-catenin displaces Groucho/TLE from Tcf/Lef by binding to a previously unidentified second, low-affinity binding site on Lef-1 that includes sequences just N-terminal to the DNA-binding domain, and that overlaps the Groucho/TLE-binding site.

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Figure 1: Transcription activation by β-catenin.
Figure 2: Regions of interaction and experimental constructs.
Figure 3: Lef-1 binding to TLE and β-catenin.
Figure 4: Disruption of the TLE-1–Lef-1–DNA complex by β-catenin.
Figure 5: β-catenin and TLE compete for binding to Lef-1.
Figure 6: Limited proteolysis of Lef-1 complexes.
Figure 7: The N terminus of Lef-1 is not required or sufficient for TLE interaction.
Figure 8: The C terminus of Lef-1 binds to TLE and to β-catenin.

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Acknowledgements

We thank M. Boulanger for assistance with the MALLS analysis, H.-J. Choi for the ITC data, S. Frydman for technical assistance and S. Stifani for TLE cDNAs. The tryptic peptide mapping was carried out by the Protein and Nucleic Acid Facility at Stanford University School of Medicine and mass spectrometry was done at the Molecular Structure Facility at University of California, Davis. This work was supported by grant GM56169 from the US National Institutes of Health to W.I.W.

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  1. Departments of Structural Biology and of Molecular & Cellular Physiology, Stanford University School of Medicine, Stanford University School of Medicine, 299 Campus Drive West, Stanford, 94305-5126, California, USA

    Danette L Daniels & William I Weis

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Correspondence to William I Weis.

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Supplementary information

Supplementary Fig. 1

MALLS analysis. (PDF 336 kb)

Supplementary Fig. 2

ITC data. (PDF 164 kb)

Supplementary Table 1

MALLS molecular mass. (PDF 60 kb)

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Daniels, D., Weis, W. β-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat Struct Mol Biol 12, 364–371 (2005). https://doi.org/10.1038/nsmb912

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