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:

Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2

Abstract

The myocyte enhancer factor-2 (MEF2) family of transcription factors has important roles in the development and function of T cells, neuronal cells and muscle cells1,2,3. MEF2 is capable of repressing or activating transcription by association with a variety of co-repressors or co-activators in a calcium-dependent manner1,4,5. Transcriptional repression by MEF2 has attracted particular attention because of its potential role in hypertrophic responses of cardiomyocytes6. Several MEF2 co-repressors, such as Cabin1/Cain and class II histone deacetylases (HDACs), have been identified7,8,9,10,11,12. However, the molecular mechanism of their recruitment to specific promoters by MEF2 remains largely unknown. Here we report a crystal structure of the MADS-box/MEF2S domain of human MEF2B bound to a motif of the transcriptional co-repressor Cabin1 and DNA at 2.2 Å resolution. The crystal structure reveals a stably folded MEF2S domain on the surface of the MADS box. Cabin1 adopts an amphipathic α-helix to bind a hydrophobic groove on the MEF2S domain, forming a triple-helical interaction. Our studies of the ternary Cabin1/MEF2/DNA complex show a general mechanism by which MEF2 recruits transcriptional co-repressor Cabin1 and class II HDACs to specific DNA sites.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Structure of the Cabin1/MEF2B/DNA complex.
Figure 2: The fully folded structure of the MADS-box/MEF2S domain.
Figure 3: The overall structure of the Cabin1-binding site of MEF2B.
Figure 4: Crystallographic and mutational analyses of the Cabin1/MEF2B interface.

Similar content being viewed by others

References

  1. Youn, H. D., Sun, L., Prywes, R. & Liu, J. O. Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2. Science 286, 790–793 (1999)

    Article  CAS  Google Scholar 

  2. Mao, Z., Bonni, A., Xia, F., Nadal-Vicens, M. & Greenberg, M. E. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286, 785–790 (1999)

    Article  CAS  Google Scholar 

  3. Black, B. L. & Olson, E. N. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu. Rev. Cell Dev. Biol. 14, 167–196 (1998)

    Article  CAS  Google Scholar 

  4. McKinsey, T. A., Zhang, C. L. & Olson, E. N. MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem. Sci. 27, 40–47 (2002)

    Article  CAS  Google Scholar 

  5. Youn, H. D., Grozinger, C. M. & Liu, J. O. Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4. J. Biol. Chem. 275, 22563–22567 (2000)

    Article  CAS  Google Scholar 

  6. Zhang, C. L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002)

    Article  CAS  Google Scholar 

  7. Youn, H. D. & Liu, J. O. Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2. Immunity 13, 85–94 (2000)

    Article  CAS  Google Scholar 

  8. McKinsey, T. A., Zhang, C. L., Lu, J. & Olson, E. N. Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408, 106–111 (2000)

    Article  ADS  CAS  Google Scholar 

  9. Sparrow, D. B. et al. MEF-2 function is modified by a novel co-repressor, MITR. EMBO J. 18, 5085–5098 (1999)

    Article  CAS  Google Scholar 

  10. Miska, E. A. et al. HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J. 18, 5099–5107 (1999)

    Article  CAS  Google Scholar 

  11. Sun, L. et al. Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity 8, 703–711 (1998)

    Article  CAS  Google Scholar 

  12. Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S. & Snyder, S. H. Cain, a novel physiologic protein inhibitor of calcineurin. J. Biol. Chem. 273, 18325–18331 (1998)

    Article  CAS  Google Scholar 

  13. Woronicz, J. D. et al. Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol. Cell. Biol. 15, 6364–6376 (1995)

    Article  CAS  Google Scholar 

  14. Santelli, E. & Richmond, T. J. Crystal structure of MEF2A core bound to DNA at 1.5 Å resolution. J. Mol. Biol. 297, 437–449 (2000)

    Article  CAS  Google Scholar 

  15. Huang, K. et al. Solution structure of the MEF2A–DNA complex: structural basis for the modulation of DNA bending and specificity by MADS-box transcription factors. EMBO J. 19, 2615–2628 (2000)

    Article  CAS  Google Scholar 

  16. Tan, S. & Richmond, T. J. Crystal structure of the yeast MATα2/MCM1/DNA ternary complex. Nature 391, 660–666 (1998)

    Article  ADS  CAS  Google Scholar 

  17. Hassler, M. & Richmond, T. J. The B-box dominates SAP-1–SRF interactions in the structure of the ternary complex. EMBO J. 20, 3018–3028 (2001)

    Article  CAS  Google Scholar 

  18. Pellegrini, L., Tan, S. & Richmond, T. J. Structure of serum response factor core bound to DNA. Nature 376, 490–498 (1995)

    Article  ADS  CAS  Google Scholar 

  19. Molkentin, J. D., Black, B. L., Martin, J. F. & Olson, E. N. Mutational analysis of the DNA binding, dimerization, and transcriptional activation domains of MEF2C. Mol. Cell. Biol. 16, 2627–2636 (1996)

    Article  CAS  Google Scholar 

  20. Molkentin, J. D., Black, B. L., Martin, J. F. & Olson, E. N. Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell 83, 1125–1136 (1995)

    Article  CAS  Google Scholar 

  21. Bjorkman, P. J. et al. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329, 506–512 (1987)

    Article  ADS  CAS  Google Scholar 

  22. Lemercier, C. et al. mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity. J. Biol. Chem. 275, 15594–15599 (2000)

    Article  CAS  Google Scholar 

  23. Lu, J., McKinsey, T. A., Nicol, R. L. & Olson, E. N. Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc. Natl Acad. Sci. USA 97, 4070–4075 (2000)

    Article  ADS  CAS  Google Scholar 

  24. Lu, J., McKinsey, T. A., Zhang, C. L. & Olson, E. N. Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol. Cell 6, 233–244 (2000)

    Article  CAS  Google Scholar 

  25. Sartorelli, V., Huang, J., Hamamori, Y. & Kedes, L. Molecular mechanisms of myogenic coactivation by p300: direct interaction with the activation domain of MyoD and with the MADS box of MEF2C. Mol. Cell. Biol. 17, 1010–1026 (1997)

    Article  CAS  Google Scholar 

  26. Otwinowski, Z. in Proceedings of the CCP4 Study Weekend (eds Sawyer, L., Isaacs, N. & Burley, S.) 56–62 (SERC Daresbury Laboratory, Daresbury, UK, 1993)

    Google Scholar 

  27. Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991)

    Article  Google Scholar 

  28. Brunger, A. T. et al. Crystallography & NMR System: A new software suite for macromolecular structure determination. Acta Crystallogr. D Biol. Crystallogr. 54, 905–921 (1998)

    Article  CAS  Google Scholar 

  29. The CCP4 suite: Programs for protein crystallography. Acta Crystallogr. D 50, 760–776 (1994)

  30. Carson, M. Ribbons 2.0. J. Appl. Crystallogr. 24, 958–961 (1991)

    Article  Google Scholar 

Download references

Acknowledgements

We thank H. Tong from APS beamline 14-BM, M. Giffin and D. Bates for help in data collection, G. Murphy, N. Ahn, J. Goodrich and D. Wuttke for critical reading of the manuscript, and T. Mckinsey for discussion. This research was supported by a scholar award from the Damon Runyon–Walter Winchell Foundation (L.C.) and grants from the W. M. Keck foundation (L.C.) and the NIH (L.C. and J.O.L.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lin Chen.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Han, A., Pan, F., Stroud, J. et al. Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2. Nature 422, 730–734 (2003). https://doi.org/10.1038/nature01555

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01555

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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