Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1α

Nature Structural Biology volume 7, pages 744–748 (2000)Cite this article

Abstract

Maturity-onset diabetes of the young type 3 (MODY3) results from mutations in the transcriptional activator hepatocyte nuclear factor-1α (HNF-1α). Several MODY3 mutations target the HNF-1α dimerization domain (HNF-p1), which binds the coactivator, dimerization cofactor of HNF-1 (DCoH). To define the mechanism of coactivator recognition and the basis for the MODY3 phenotype, we determined the cocrystal structure of the DCoH–HNF-p1 complex and characterized biochemically the effects of MODY3 mutations in HNF-p1. The DCoH–HNF-p1 complex comprises a dimer of dimers in which HNF-p1 forms a unique four-helix bundle. Through rearrangements of interfacial side chains, a single, bifunctional interface in the DCoH dimer mediates both HNF-1α binding and formation of a competing, transcriptionally inactive DCoH homotetramer. Consistent with the structure, MODY3 mutations in HNF-p1 reduce activator function by two distinct mechanisms.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Stereo view of the experimental, MAD-phased 2.6 Å resolution, electron density map contoured at 1 σ superimposed on the refined model.
Figure 2: Structure of the DCoH–HNF-p1 complex.
Figure 3: Bifunctional recognition surface of DCoH supports a model for autoinhibition of coactivator function.
Figure 4: Effects of MODY3 mutations in the HNF-1α dimerization domain.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Struhl, K. Cell 98, 1–4 (1999).

    Article  CAS  Google Scholar 

  2. Myers, L.C., Gustafsson, C.M., Hayashibara, K.C., Brown, P.O. & Kornberg, R.D. Proc. Natl. Acad. Sci. USA 96, 67–72 (1999).

    Article  CAS  Google Scholar 

  3. Naar, A.M. et al. Nature 398, 828–832 (1999).

    Article  CAS  Google Scholar 

  4. Rojas, J.R. et al. Nature 401, 93–98 (1999).

    Article  CAS  Google Scholar 

  5. Perini, G., Oetjen, E. & Green, M.R., J. Biol. Chem. 274, 13970–13977 (1999).

    Article  CAS  Google Scholar 

  6. Perini, G., Wagner, S. & Green, M.R. Nature 376, 602–605 (1995).

    Article  CAS  Google Scholar 

  7. Riese, J. et al. Cell 88, 777–787 (1997).

    Article  CAS  Google Scholar 

  8. Luo, Y., Ge, H., Stevens, S., Xiao, H. & Roeder, R.G. Mol. Cell. Biol. 18, 3803–3810 (1998).

    Article  CAS  PubMed Central  Google Scholar 

  9. Mendel, D.B. et al. Science 254, 1762–1767 (1991).

    Article  CAS  Google Scholar 

  10. Emens, L.A., Landers, D.W. & Moss, L.G. Biochemistry 89, 7300–7304 (1992).

    CAS  Google Scholar 

  11. Mendel, D.B. & Crabtree, G.R. J. Biol. Chem. 266, 677–680 (1991).

    CAS  PubMed  Google Scholar 

  12. Citron, B.A. et al. Proc. Natl. Acad. Sci. USA 89, 11891–11894 (1992).

    Article  CAS  Google Scholar 

  13. De Francesco, R., Pastore, A., Vecchio, G. & Cortese, R. Biochemistry 30, 143–147 (1991).

    Article  CAS  Google Scholar 

  14. Cronk, J.D. Structural studies of DCoH, a bifunctional enzyme and protein-binding transcriptional coactivator. (Ph.D. Thesis, University of California, Berkeley; 1996).

    Google Scholar 

  15. Holm, L. & Sander, C. J. Mol. Biol. 233, 123–138 (1993).

    Article  CAS  PubMed Central  Google Scholar 

  16. Hua, Q. et al. Proc. Natl. Acad. Sci. USA 97, 1999–2004 (2000).

    Article  CAS  Google Scholar 

  17. Pastore, A. et al. Biochemistry 30, 148–153 (1991).

    Article  CAS  Google Scholar 

  18. Pastore, A., De Francesco, R., Castiglione, M.M.A., Nalis, D. & Cortese, R. Protein Eng. 5, 749–757 (1992).

    Article  CAS  Google Scholar 

  19. Nicosia, A. et al. Cell 61, 1225–1236 (1990).

    Article  CAS  Google Scholar 

  20. Endrizzi, J.A., Cronk, J.D., Weidong, W., Crabtree, G.R. & Alber, T., Science 268, 556–559 (1995).

    Article  CAS  Google Scholar 

  21. Johnen, G. & Kaufman, S. Proc. Natl. Acad. Sci. USA 94, 13469–13474 (1997).

    Article  CAS  Google Scholar 

  22. Ficner, R., Sauer, U.H., Stier, G. & Suck, D. EMBO J 14, 2034–2042 (1995).

    Article  CAS  PubMed Central  Google Scholar 

  23. Eckert, D.M., Malashkevich, V.N., Hong, L.H., Carr, P.A. & Kim, P.S. Cell 99, 103–115 (1999).

    Article  CAS  Google Scholar 

  24. McWhirter, S.M. et al. Proc. Natl. Acad. Sci. USA 96, 8408–8413 (1999).

    Article  CAS  Google Scholar 

  25. Ye, H., Park, Y.C., Kreishman, M., Kieff, E. & Wu, H., Mol. Cell 4, 321–330 (1999).

    Article  CAS  Google Scholar 

  26. Cronk, J.D., Endrizzi, J.A. & Alber, T. Protein Sci. 5, 1963–1972 (1996).

    Article  CAS  PubMed Central  Google Scholar 

  27. Rebrin, I., Thöny, B., Bailey, S.W. & Ayling, J.E. Biochemistry 37, 11246–11254 (1998).

    Article  CAS  Google Scholar 

  28. Koster, S. et al. Eur. J. Biochem. 241, 858–864 (1996).

    Article  CAS  Google Scholar 

  29. Rhee, K., Stier, G., Becker, P.B., Suck, D. & Sandaltzopoulos, R. J. Mol. Biol. 265, 20–29 (1997).

    Article  CAS  Google Scholar 

  30. Radhakrishnan, I. et al. Cell 1997, 741–752 (1997).

    Article  Google Scholar 

  31. Darimont, B.D. et al. Genes Dev. 12, 3343–3356 (1998).

    Article  CAS  PubMed Central  Google Scholar 

  32. Nolte, R.T. et al., Nature 395, 137–143 (1998).

    Article  CAS  Google Scholar 

  33. De Vos, A.M., Ultsch, M. & Kossiakoff, A.A. Science 255, 306–312 (1992).

    Article  CAS  Google Scholar 

  34. Yamagata, K. et al. Nature 384, 455–458 (1996).

    Article  CAS  Google Scholar 

  35. Iwasaki, N. et al. Diabetes 46, 1504–1508 (1997).

    Article  CAS  Google Scholar 

  36. Boutin, P. et al. Diabetes 46, 2108–2109 (1997).

    Article  CAS  Google Scholar 

  37. Ng, M.C. et al. Diabetic Med. 16, 956–963 (1999).

    Article  CAS  Google Scholar 

  38. Kuo, C.J. et al. Nature 355, 457–461 (1992).

    Article  CAS  Google Scholar 

  39. Gragnoli, C. et al. Diabetes 46, 1648–1651 (1997).

    Article  CAS  Google Scholar 

  40. Van Duyne, G.D., Standaert, R.F., Karplus, P.A., Schreiber, S.L. & Clardy, J. J. Mol. Biol. 229, 105–124 (1993).

    Article  CAS  Google Scholar 

  41. Leslie, A.G.W., Brick, P. & Wonacott, A. Daresbury Lab. Information Quart. Protein Crystallogr. 18, 33–39 (1986).

    Google Scholar 

  42. Knight, S. Rubulose 1,5-bisphosphate carboxylase/oxygenase — a structural study (PhD Thesis Swedish University of Agricultural Sciences Uppsala; 1989).

    Google Scholar 

  43. La Fortelle, E. & Bricogne, G. Methods Enzymol. 276, 472–494 (1997)

    Article  PubMed Central  Google Scholar 

  44. Jones, T.A., Zhou, J.Y., Cowan, S.W. & Kjeldgaard, M. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

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

    Article  PubMed Central  Google Scholar 

  46. Lassar, A.B. et al. Cell 66, 305–315 (1991).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D.S. King for peptide synthesis and mass spectrometry. Data were collected at the Stanford Synchrotron Radiation Laboratory (SSRL) with the help of H. Bellamy. SSRL is operated by the Department of Energy, Office of Basic Energy Sciences. The SSRL Biotechnology Program is supported by the NIH National Center for Research Resources. R.B.R. was supported by postdoctoral fellowships from the NIH and the Juvenile Diabetes Foundation International. This research was supported by a grant from the NIH (T.A.).

Author information

Author notes

  1. Jeff D. Cronk

    Present address: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, P.O. Box 19024, Seattle, Washington, 98109-1024, USA

Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California, Berkeley, 94720-3206, California, USA

    Robert B. Rose, James A. Endrizzi, Jeff D. Cronk & Tom Alber

  2. Howard Hughes Medical Institute, Beckman Center for Molecular and Genetic Medicine, Stanford University, Stanford, 94305, California, USA

    J. Henri Bayle & Gerald R. Crabtree

Authors
  1. Robert B. Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Henri Bayle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James A. Endrizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeff D. Cronk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gerald R. Crabtree
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tom Alber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tom Alber.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rose, R., Bayle, J., Endrizzi, J. et al. Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1α. Nat Struct Mol Biol 7, 744–748 (2000). https://doi.org/10.1038/78966

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/78966

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing