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Tcf4 can specifically recognize β-catenin using alternative conformations

Nature Structural Biology volume 8, pages 1048–1052 (2001)Cite this article

Abstract

Accumulation of the Wnt pathway effector β-catenin is a hallmark of a number of cancers, including colon cancer. As β-catenin accumulates in the cell, it forms a complex with Tcf family transcription factors and activates the transcription of several critical genes involved in cell proliferation. Because Tcf4 is the predominant Tcf factor present in colon cancer cells, drugs that specifically disrupt the β-catenin–Tcf4 complex could be useful in treating colon cancers. Earlier structural and biochemical studies demonstrated that the central region of the β-catenin binding domain of Tcf is essential for anchoring Tcf to β-catenin via two conserved lysines in β-catenin (called the charged 'buttons'). Here we report the crystal structure of a β-catenin–Tcf4 complex at 2.0 Å resolution. Our structural and mutagenesis studies show that Tcf4 docks specifically to β-catenin using several distinct conformations in its essential central region. These conformations allow different glutamate residues in the central region of Tcf4 to form a salt bridge with the same critical charged button, Lys 312 of β-catenin. We propose that this interaction may be the first event in β-catenin–Tcf4 recognition.

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Figure 1: Overall structure of the hTcf4-CBD–β-catenin armadillo repeat complex.
Figure 2: Comparison of the structural conformations of hTcf4 and XTcf3 near the second charged button (Lys 312).
Figure 3: Interaction between the second button of β-catenin and the Glu residues in hTcf4.
Figure 4: The N-terminus of Tcf is required for the binding to β-catenin.

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Acknowledgements

We wish to thank A.M. Kral and C.A. Omer (Merck) for the Tcf4 construct, and E. Merritt, C. Verlinda, R. Klevit and R. Moon for critical comments on the manuscript. This work was supported by NIH grants to D.K. and W.X. T.G. was supported by a NIH training grant. Diffraction data were collected at the Advanced Photon Source of Argonne National Laboratory, which is supported by the NIH and NSF.

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  1. Thomas A. Graham, Denise M. Ferkey, Feng Mao and David Kimelman: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Structure, University of Washington, Seattle, 98195, Washington, USA

    Thomas A. Graham, Feng Mao & Wenqing Xu

  2. Biomolecular Structure Design Program, University of Washington, Seattle, 98195, Washington, USA

    Thomas A. Graham

  3. Department of Biochemistry, University of Washington, Seattle, 98195, Washington, USA

    Denise M. Ferkey & David Kimelman

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Correspondence to Wenqing Xu.

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Graham, T., Ferkey, D., Mao, F. et al. Tcf4 can specifically recognize β-catenin using alternative conformations. Nat Struct Mol Biol 8, 1048–1052 (2001). https://doi.org/10.1038/nsb718

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