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:

Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9

Nature volume 416, pages 103–107 (2002)Cite this article

Abstract

Specific modifications to histones are essential epigenetic markers1—heritable changes in gene expression that do not affect the DNA sequence. Methylation of lysine 9 in histone H3 is recognized by heterochromatin protein 1 (HP1), which directs the binding of other proteins to control chromatin structure and gene expression2,3,4. Here we show that HP1 uses an induced-fit mechanism for recognition of this modification, as revealed by the structure of its chromodomain bound to a histone H3 peptide dimethylated at Nζ of lysine 9. The binding pocket for the N-methyl groups is provided by three aromatic side chains, Tyr 21, Trp 42 and Phe 45, which reside in two regions that become ordered on binding of the peptide. The side chain of Lys 9 is almost fully extended and surrounded by residues that are conserved in many other chromodomains. The QTAR peptide sequence preceding Lys 9 makes most of the additional interactions with the chromodomain, with HP1 residues Val 23, Leu 40, Trp 42, Leu 58 and Cys 60 appearing to be a major determinant of specificity by binding the key buried Ala 7. These findings predict which other chromodomains will bind methylated proteins and suggest a motif that they recognize.

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: Structure of the HP1β chromodomain complexed with a histone H3 peptide dimethylated at lysines 4 and 9.
Figure 2: The interface between the chromodomain and the methylated peptide.
Figure 3: Sequence comparisons and residues involved in complex formation.

Similar content being viewed by others

References

  1. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000)

    Article  ADS  CAS  Google Scholar 

  2. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001)

    Article  ADS  CAS  Google Scholar 

  3. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001)

    Article  ADS  CAS  Google Scholar 

  4. Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D. & Grewal, S. I. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292, 110–113 (2001)

    Article  ADS  CAS  Google Scholar 

  5. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001)

    Article  CAS  Google Scholar 

  6. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000)

    Article  ADS  CAS  Google Scholar 

  7. Noma, K., Allis, C. D. & Grewal, S. I. Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science 293, 1150–1155 (2001)

    Article  CAS  Google Scholar 

  8. Litt, M. D., Simpson, M., Gaszner, M., Allis, C. D. & Felsenfeld, G. Correlation between histone lysine methylation and developmental changes at the chicken β-globin locus. Science 293, 2453–2455 (2001)

    Article  ADS  CAS  Google Scholar 

  9. Nielsen, S. J. et al. Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561–565 (2001)

    Article  ADS  CAS  Google Scholar 

  10. Ball, L. J. et al. Structure of the chromatin binding (chromo) domain from mouse modifier protein 1. EMBO J. 16, 2473–2481 (1997)

    Article  CAS  Google Scholar 

  11. Brasher, S. V. et al. The structure of mouse HP1 suggests a unique mode of single peptide recognition by the shadow chromo domain dimer. EMBO J. 19, 1587–1597 (2000)

    Article  CAS  Google Scholar 

  12. Horita, D. A., Ivanova, A. V., Altieri, A. S., Klar, A. J. & Byrd, R. A. Solution structure, domain features, and structural implications of mutants of the chromo domain from the fission yeast histone methyltransferase Clr4. J. Mol. Biol. 307, 861–870 (2001)

    Article  CAS  Google Scholar 

  13. Cowieson, N. P., Partridge, J. F., Allshire, R. C. & McLaughlin, P. J. Dimerisation of a chromo shadow domain and distinctions from the chromodomain as revealed by structural analysis. Curr. Biol. 10, 517–525 (2000)

    Article  CAS  Google Scholar 

  14. Akhtar, A., Zink, D. & Becker, P. B. Chromodomains are protein–RNA interaction modules. Nature 407, 405–409 (2000)

    Article  ADS  CAS  Google Scholar 

  15. Jacobs, S. A. et al. Specificity of the HP1 chromo domain for the methylated N-terminus of histone H3. EMBO J. 20, 5232–5241 (2001)

    Article  CAS  Google Scholar 

  16. Platero, J. S., Hartnett, T. & Eissenberg, J. C. Functional analysis of the chromo domain of HP1. EMBO J. 14, 3977–3986 (1995)

    Article  CAS  Google Scholar 

  17. Means, G. E. & Feeney, R. E. Reductive alkylation of amino groups in proteins. Biochemistry 7, 2192–2201 (1968)

    Article  CAS  Google Scholar 

  18. Ferentz, A. E. & Wagner, G. NMR: A multifaceted approach to macromolecular structure. Q. Rev. Biophys. 33, 29–65 (2000)

    Article  CAS  Google Scholar 

  19. Zwahlen, C. et al. Methods for measurement of intermolecular NOEs by multinuclear NMR spectroscopy: Application to a bacteriophage λ N-peptide/boxB RNA complex. J. Am. Chem. Soc. 119, 6711–6721 (1997)

    Article  CAS  Google Scholar 

  20. Melacini, G. Separation of intra- and intermolecular NOEs through simultaneous editing and J-compensated filtering: A quadrature-free constant-time J-resolved approach. J. Am. Chem. Soc. 122, 9735–9738 (2000)

    Article  CAS  Google Scholar 

  21. Kraulis, P. J. et al. The solution structure and dynamics of ras p21.GDP determined by heteronuclear three- and four-dimensional NMR spectroscopy. Biochemistry 33, 3515–3531 (1994)

    Article  CAS  Google Scholar 

  22. Brunger, A. T. et al. Crystallography and NMR system (CNS): A new software system for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998)

    Article  CAS  Google Scholar 

  23. Linge, J. P., O'Donoghue, S. J. & Nilges, M. Automated assignment of ambiguous NOEs with ARIA. Methods Enzymol. 339, 71–90 (2001)

    Article  CAS  Google Scholar 

  24. Cornilescu, G., Delaglio, F. & Bax, A. Protein backbone angle restraints from searching a database for chemical shift and sequence homology. J. Biol. NMR 13, 289–302 (1999)

    Article  CAS  Google Scholar 

  25. Kraulis, P. J. MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 24, 946–950 (1991)

    Article  Google Scholar 

  26. Merrit, E. A. & Murphy, M. E. P. Raster3D Version 2.0. A program for photorealistic molecular graphics. Acta Crystallogr. D 50, 869–873 (1994)

    Article  Google Scholar 

  27. Barton, G. J. ALSCRIPT: a tool to format multiple sequence alignments. Protein Eng. 6, 37–40 (1993)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Verreault for the pGEX-H3 construct; R. Turner, P. Sharratt and the PNAC facility for mass spectrometry and amino-acid analysis; A. Thiru for comments on the manuscript; the Medical Research Council for a Career Development Award (to H.R.M.); and the Wellcome Trust for financial support. The Cambridge Centre for Molecular Recognition is supported by the Biotechnology and Biological Sciences Research Council and the Wellcome Trust.

Author information

Authors and Affiliations

  1. Cambridge Centre for Molecular Recognition, Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA

    Peter R. Nielsen, Daniel Nietlispach, Helen R. Mott, Juliana Callaghan, Natalia V. Murzina & Ernest D. Laue

  2. Wellcome/Cancer Research UK, Institute of Cancer and Developmental Biology and Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QR, Cambridge, UK

    Andrew Bannister & Tony Kouzarides

  3. MRC Centre for Protein Engineering, Hills Road, Cambridge, CB2 2QH, UK

    Alexey G. Murzin

Authors
  1. Peter R. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Nietlispach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helen R. Mott
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juliana Callaghan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew Bannister
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tony Kouzarides
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexey G. Murzin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Natalia V. Murzina
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ernest D. Laue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Natalia V. Murzina or Ernest D. Laue.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nielsen, P., Nietlispach, D., Mott, H. et al. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416, 103–107 (2002). https://doi.org/10.1038/nature722

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature722

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

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