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Structure of a human Tcf4–β-catenin complex

Abstract

The multifunctional protein β-catenin is important for cell adhesion, because it binds cadherins, and the Wnt signal transduction pathway, where it interacts with the Adenomatous polyposis coli (APC) protein and TCF/Lef family transcription factors. Mutations in APC or in β-catenin are estimated to trigger formation of over 90% of all colon cancers. In colonic epithelia, these mutations produce elevated levels of Tcf4–β-catenin, which stimulates a transcriptional response that initiates polyp formation and eventually malignant growth. Thus, disruption of the Tcf4–β-catenin interaction may be an attractive goal for therapeutic intervention. Here we describe the crystal structure of a human Tcf4–β-catenin complex and compare it with recent structures of β-catenin in complex with Xenopus Tcf3 (XTcf3) and mammalian E-cadherin. The structure reveals anticipated similarities with the closely related XTcf3 complex but unexpectedly lacks one component observed in the XTcf3 structure.

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Figure 1: Structure of the Tcf4–β-catenin complex.
Figure 2: The Tcf4 extended region binds a positively charged groove.
Figure 3: Results of a representative cell transfection experiment assessing the activity of Tcf4 mutants in activating the Tcf-dependent reporter construct OT (containing three Tcf binding sites).
Figure 4: Comparison of β-catenin complexes.

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References

  1. Kinzler, K.W. & Vogelstein, B. Cell 87, 159–170 (1996).

    Article  CAS  Google Scholar 

  2. Molenaar, M. et al. Cell 86, 391–399 (1996).

    Article  CAS  Google Scholar 

  3. Behrens, J. et al. Nature 382, 638–642 (1996).

    Article  CAS  Google Scholar 

  4. Cavallo, R.A. et al. Nature 395, 604–608 (1998).

    Article  CAS  Google Scholar 

  5. Roose, J. et al. Nature 395, 608–612 (1998).

    Article  CAS  Google Scholar 

  6. van de Wetering, M. et al. Cell 88, 789–799 (1997).

    Article  CAS  Google Scholar 

  7. Korinek, V. et al. Science 275, 1784–1787 (1997).

    Article  CAS  Google Scholar 

  8. Shih, I.M., Yu, J., He, T.C., Vogelstein, B. & Kinzler, K.W. Cancer Res. 60, 1671–1676 (2000).

    CAS  PubMed  Google Scholar 

  9. Korinek, V. et al. Mol. Cell Biol. 18, 1248–1256 (1998).

    Article  CAS  Google Scholar 

  10. Korinek, V. et al. Nature Genet. 19, 379–383 (1998).

    Article  CAS  Google Scholar 

  11. Peifer, M. & Polakis, P. Science 287, 1606–1609 (2000).

    Article  CAS  Google Scholar 

  12. Barker, N., Morin, P.J. & Clevers, H. Adv. Cancer Res. 77, 1–24 (2000).

    CAS  PubMed  Google Scholar 

  13. Peifer, M., Berg, S. & Reynolds, A.B. Cell 76, 789–791 (1994).

    Article  CAS  Google Scholar 

  14. Behrens, J. et al. Science 280, 596–599 (1998).

    Article  CAS  Google Scholar 

  15. von Kries, J.P. et al. Nature Struct. Biol. 7, 800–807 (2000).

    Article  CAS  Google Scholar 

  16. Hulsken, J., Birchmeier, W. & Behrens, J. J. Cell Biol. 127, 2061–2069 (1994).

    Article  CAS  Google Scholar 

  17. Rubinfeld, B., Souza, B., Albert, I., Munemitsu, S. & Polakis, P. J. Biol. Chem. 270, 5549–5555 (1995).

    Article  CAS  Google Scholar 

  18. Huber, A.H., Nelson, W.J. & Weis, W.I. Cell 90, 871–882 (1997).

    Article  CAS  Google Scholar 

  19. Graham, T.A., Weaver, C., Mao, F., Kimelman, D. & Xu, W. Cell 103, 885–896 (2000).

    Article  CAS  Google Scholar 

  20. Huber, A.H. & Weis, W.I. Cell 105, 391–402 (2001).

    Article  CAS  Google Scholar 

  21. Omer, C.A., Miller, P.J., Diehl, R.E. & Kral, A.M. Biochem. Biophys. Res. Commun. 256, 584–590 (1999).

    Article  CAS  Google Scholar 

  22. Hsu, S.C., Galceran, J. & Grosschedl, R. Mol. Cell Biol. 18, 4807–4818 (1998).

    Article  CAS  Google Scholar 

  23. Knapp, S. et al. J. Mol. Biol. 306, 1179–1189 (2001).

    Article  CAS  Google Scholar 

  24. Hofmann, K., Bucher, P., Falquet, L. & Bairoch, A. Nucleic Acids Res. 27, 215–219 (1999).

    Article  CAS  Google Scholar 

  25. Graham, T.A., Ferkey, D.M., Mao, F., Kimelman, D. & Xu, W. Nature Struct. Biol. 11, 1048–1052 (2001).

    Article  Google Scholar 

  26. Simcha, I. et al. Mol. Biol. Cell. 12, 1177–1188 (2001).

    Article  CAS  Google Scholar 

  27. Kabsch, W. J. Appl. Crystallogr. 21, 916–924 (1988).

    Article  CAS  Google Scholar 

  28. Brünger, A.T. et al. Acta Crystallogr D 54, 905–921 (1998).

    Article  Google Scholar 

  29. Jones, T.A. & Kjeldgaard, M. Methods Enzymol. 277, 173–208 (1997).

    Article  CAS  Google Scholar 

  30. Lamzin, V.S. & Wilson, K.S. Methods Enzymol. 277, 269–305 (1997).

    Article  CAS  Google Scholar 

  31. Vajdos, F.F., Yoo, S., Houseweart, M., Sundquist, W.I. & Hill, C.P. Protein Sci. 6, 2297–2307 (1997).

    Article  CAS  Google Scholar 

  32. da Costa, L.T. et al. Oncogene 18, 5010–5014 (1999).

    Article  CAS  Google Scholar 

  33. Kraulis, P.J. J. Appl. Crystallogr. 24, 946–950 (1991).

    Article  Google Scholar 

  34. Nicholls, A., Sharp, K.A. & Honig, B. Proteins Struct. Funct. Genet. 11, 281–296 (1991).

    Article  CAS  Google Scholar 

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Correspondence to Michael J. Eck.

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Poy, F., Lepourcelet, M., Shivdasani, R. et al. Structure of a human Tcf4–β-catenin complex. Nat Struct Mol Biol 8, 1053–1057 (2001). https://doi.org/10.1038/nsb720

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