Hot spots in β-catenin for interactions with LEF-1, conductin and APC

Abstract

Interactions between β-catenin and LEF-1/TCF, APC and conductin/axin are essential for wnt-controlled stabilization of β-catenin and transcriptional activation. The wnt signal transduction pathway is important in both embryonic development and tumor progression. We identify here amino acid residues in β-catenin that distinctly affect its binding to LEF-1/TCF, APC and conductin. These residues form separate surface clusters, termed hot spots, along the armadillo superhelix of β-catenin. We also show that complementary charged and hydrophobic amino acids are required for formation of the bipartite β-catenin–LEF-1 transcription factor. Moreover, we demonstrate that conductin/axin binding to β-catenin is essential for β-catenin degradation, and that APC acts as a cofactor of conductin/axin in this process. Binding of APC to conductin/axin activates the latter and occurs between their SAMP and RGS domains, respectively.

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Figure 1: In vitro mutagenesis of the armadillo domain of β-catenin.
Figure 3: Hot spots in β-catenin for LEF-1, APC or conductin binding.
Figure 2: Mutations in β-catenin that block LEF-1, APC or conductin binding.
Figure 4: Amino acids in LEF-1 essential for β-catenin binding.
Figure 5: Conductin-induced or APC-induced degradation of β-catenin mutants.
Figure 6: Conductin and APC synergize phosphorylation of β-catenin.

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Acknowledgements

We would like to thank C. Birchmeier (Berlin), A.H. Huber and W.I. Weis (Stanford) for critical reading of the manuscript and for helpful discussions, H. Clevers (Utrecht) for the IIA1.6 cells and reporter constructs, W. Altenhofen (Ludwigshafen), J. Joachim Müller and T. Schwartz (Berlin) for help with the analysis of structural data of β-catenin, and the Deutsche Forschungsgemeinschaft for financial support.

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Correspondence to Walter Birchmeier.

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von Kries, J., Winbeck, G., Asbrand, C. et al. Hot spots in β-catenin for interactions with LEF-1, conductin and APC. Nat Struct Mol Biol 7, 800–807 (2000). https://doi.org/10.1038/79039

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