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.

  • Article
  • Published:

A TAF4-homology domain from the corepressor ETO is a docking platform for positive and negative regulators of transcription

Nature Structural & Molecular Biology volume 14, pages 653–661 (2007)Cite this article

Abstract

The eight twenty-one protein, ETO, is implicated in 12%–15% of acute human leukemias as part of a gene fusion with RUNX1 (also called AML1). Of the four ETO domains related to Drosophila melanogaster Nervy, only two are required to induce spontaneous myeloid leukemia upon transplantation into the mouse. One of these domains is related in sequence to TAF4, a component of TFIID. The structure of this domain, ETO-TAFH, is similar to yeast Rpb4 and to Escherichia coli σ70; it is the first TAF-related protein with structural similarity to the multisubunit RNA polymerases. Overlapping surfaces of ETO-TAFH interact with an autonomous repression domain of the nuclear receptor corepressor N-CoR and with a conserved activation domain from the E-box family of transcription factors. Thus, ETO-TAFH acts as a structural platform that can interchange negative and positive coregulatory proteins to control transcription.

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: Conserved domains of ETO and its relationship to TAF4.
Figure 2: Three-dimensional structure of ETO-TAFH.
Figure 3: Spectral analysis of ETO-TAFH F136Y.
Figure 4: ETO-TAFH is structurally homologous to integral subunits of the prokaryotic and eukaryotic RNA polymerases.
Figure 5: ETO-TAFH engages autonomous regulatory domains of the nuclear hormone receptor corepressor N-CoR and the E-box protein E2A.
Figure 6: Modeling of the interaction between N-CoR-R1 and HEB-AD1 bound to ETO-TAFH.

Similar content being viewed by others

Accession codes

Primary accessions

Protein Data Bank

Referenced accessions

Protein Data Bank

References

  1. Davis, J.N., McGhee, L. & Meyers, S. The ETO (MTG8) gene family. Gene 303, 1–10 (2003).

    Article  CAS  Google Scholar 

  2. Miyoshi, H. et al. t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc. Natl. Acad. Sci. USA 88, 10431–10434 (1991).

    Article  CAS  Google Scholar 

  3. Miyoshi, H. et al. The t(8;21) translocation in acute myeloid leukemia results in production of an AML1–MTG8 fusion transcript. EMBO J. 12, 2715–2721 (1993).

    Article  CAS  Google Scholar 

  4. Erickson, P. et al. Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood 80, 1825–1831 (1992).

    CAS  PubMed  Google Scholar 

  5. Gamou, T. et al. The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family. Blood 91, 4028–4037 (1998).

    CAS  PubMed  Google Scholar 

  6. Look, A.T. Oncogenic transcription factors in the human acute leukemias. Science 278, 1059–1064 (1997).

    Article  CAS  Google Scholar 

  7. Gelmetti, V. et al. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol. Cell. Biol. 18, 7185–7191 (1998).

    Article  CAS  Google Scholar 

  8. Lutterbach, B. et al. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol. Cell. Biol. 18, 7176–7184 (1998).

    Article  CAS  Google Scholar 

  9. Wang, J., Hoshino, T., Redner, R.L., Kajigaya, S. & Liu, J.M. ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc. Natl. Acad. Sci. USA 95, 10860–10865 (1998).

    Article  CAS  Google Scholar 

  10. Lausen, J., Cho, S., Liu, S. & Werner, M.H. The nuclear receptor co-repressor (N-CoR) utilizes repression domains I and III for interaction and co-repression with ETO. J. Biol. Chem. 279, 49281–49288 (2004).

    Article  CAS  Google Scholar 

  11. Minucci, S. et al. Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol. Cell 5, 811–820 (2000).

    Article  CAS  Google Scholar 

  12. Zhang, J. et al. Oligomerization of ETO is obligatory for corepressor interaction. Mol. Cell. Biol. 21, 156–163 (2001).

    Article  CAS  Google Scholar 

  13. Liu, Y. et al. The tetramer structure of the Nervy homology two domain, NHR2, is critical for AML1/ETO's activity. Cancer Cell 9, 249–260 (2006).

    Article  Google Scholar 

  14. Hiebert, S.W., Lutterbach, B. & Amann, J. Role of co-repressors in transcriptional repression mediated by the t(8;21), t(16;21), t(12;21), and inv(16) fusion proteins. Curr. Opin. Hematol. 8, 197–200 (2001).

    Article  CAS  Google Scholar 

  15. Lausen, J., Liu, S., Fliegauf, M., Lubbert, M. & Werner, M.H. ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO. Oncogene 25, 1349–1357 (2006).

    Article  CAS  Google Scholar 

  16. Shimada, H. et al. Analysis of genes under the downstream control of the t(8;21) fusion protein AML1–MTG8: overexpression of the TIS11b (ERF-1, cMG1) gene induces myeloid cell proliferation in response to G-CSF. Blood 96, 655–663 (2000).

    CAS  PubMed  Google Scholar 

  17. Andersson, A. et al. Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations. Leukemia 19, 1042–1050 (2005).

    Article  CAS  Google Scholar 

  18. Dunne, J. et al. siRNA-mediated AML1/MTG8 depletion affects differentiation and proliferation-associated gene expression in t(8;21)-positive cell lines and primary AML blasts. Oncogene 25, 6067–6078 (2006).

    Article  CAS  Google Scholar 

  19. Yan, M. et al. Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. Proc. Natl. Acad. Sci. USA 101, 17186–17191 (2004).

    Article  CAS  Google Scholar 

  20. Rhoades, K.L. et al. Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model. Blood 96, 2108–2115 (2000).

    CAS  PubMed  Google Scholar 

  21. Yuan, Y. et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc. Natl. Acad. Sci. USA 98, 10398–10403 (2001).

    Article  CAS  Google Scholar 

  22. Higuchi, M. et al. Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 1, 63–74 (2002).

    Article  CAS  Google Scholar 

  23. de Guzman, C.G. et al. Hematopoietic stem cell expansion and distinct myeloid developmental abnormalities in a murine model of the AML1-ETO translocation. Mol. Cell. Biol. 22, 5506–5517 (2002).

    Article  CAS  Google Scholar 

  24. Amann, J.M. et al. ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain. Mol. Cell. Biol. 21, 6470–6483 (2001).

    Article  CAS  Google Scholar 

  25. Zhang, J., Kalkum, M., Yamamura, S., Chait, B.T. & Roeder, R.G. E protein silencing by the leukemogenic AML1-ETO fusion protein. Science 305, 1286–1289 (2004).

    Article  CAS  Google Scholar 

  26. Malhotra, A., Severinova, E. & Darst, S.A. Crystal structure of a sigma 70 subunit fragment from E. coli RNA polymerase. Cell 87, 127–136 (1996).

    Article  CAS  Google Scholar 

  27. Armache, K.J., Mitterweger, S., Meinhart, A. & Cramer, P. Structures of complete RNA polymerase II and its subcomplex, Rpb4/7. J. Biol. Chem. 280, 7131–7134 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Güntert, P. Automated NMR structure calculation with CYANA. Methods Mol. Biol. 278, 353–378 (2004).

    Google Scholar 

  30. Schwieters, C.D., Kuszewski, J.J., Tjandra, N. & Clore, G.M. The Xplor-NIH NMR molecular structure determination package. J. Magn. Reson. 160, 65–73 (2003).

    Article  CAS  Google Scholar 

  31. Clore, G.M. & Garrett, D.S. R-factor, Free R and complete cross-validation for dipolar coupling refinement of NMR structures. J. Am. Chem. Soc. 121, 9008–9012 (1999).

    Article  CAS  Google Scholar 

  32. Spronk, C.A., Linge, J.P., Hilbers, C.W. & Vuister, G.W. Improving the quality of protein structures derived by NMR spectroscopy. J. Biomol. NMR 22, 281–289 (2002).

    Article  CAS  Google Scholar 

  33. Plevin, M.J., Zhang, J., Guo, C., Roeder, R.G. & Ikura, M. The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain. Proc. Natl. Acad. Sci. USA 103, 10242–10247 (2006).

    Article  CAS  Google Scholar 

  34. Nomura, M., Uda-Tochio, H., Murai, K., Mori, N. & Nishimura, Y. The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 corepressor by using its distinct short hydrophobic helix. J. Mol. Biol. 354, 903–915 (2005).

    Article  CAS  Google Scholar 

  35. Swanson, K.A. et al. HBP1 and Mad1 repressors bind the Sin3 co-repressor PAH2 domain with opposite helical orientations. Nat. Struct. Mol. Biol. 11, 738–746 (2004).

    Article  CAS  Google Scholar 

  36. Spronk, C.A. et al. The Mad1-Sin3B interaction involves a novel helical fold. Nat. Struct. Biol. 7, 1100–1104 (2000).

    Article  CAS  Google Scholar 

  37. Kolodziej, P.A., Woychik, N., Liao, S.M. & Young, R.A. RNA polymerase II subunit composition, stoichiometry, and phosphorylation. Mol. Cell. Biol. 10, 1915–1920 (1990).

    Article  CAS  Google Scholar 

  38. Choder, M. Rpb4 and Rpb7: subunits of RNA polymerase II and beyond. Trends Biochem. Sci. 29, 674–681 (2004).

    Article  CAS  Google Scholar 

  39. Petermann, R. et al. Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II. Oncogene 17, 603–610 (1998).

    Article  CAS  Google Scholar 

  40. Beier, D., Spohn, G., Rappuoli, R. & Scarlato, V. Functional analysis of the H. pylori principal sigma subunit of RNA polymerase reveals that the spacer region is important for efficient transcription. Mol. Microbiol. 30, 121–134 (1998).

    Article  CAS  Google Scholar 

  41. Murre, C. Helix-loop-helix proteins and lymphocyte development. Nat. Immunol. 6, 1079–1086 (2005).

    Article  CAS  Google Scholar 

  42. Massari, M.E., Jennings, P.A. & Murre, C. The AD1 transactivation domain of E2A contains a highly conserved helix which is required for its activity in both Saccharomyces cerevisiae and mammalian cells. Mol. Cell. Biol. 16, 121–129 (1996).

    Article  CAS  Google Scholar 

  43. Dominguez, C., Boelens, R. & Bonvin, A.M.J.J. HADDOCK: a protein-protein docking approach based on biochemical and/or biophysical information. J. Am. Chem. Soc. 125, 1731–1737 (2003).

    Article  CAS  Google Scholar 

  44. Zor, T., DeGuzman, R.N., Dyson, H.J. & Wright, P.E. Solution structure of the KIX domain of CBP bound to the transactivation domain of c-Myb. J. Mol. Biol. 337, 521–534 (2004).

    Article  CAS  Google Scholar 

  45. Perissi, V. & Rosenfeld, M.G. Controlling nuclear receptors: the circular logic of cofactor cycles. Nat. Rev. Mol. Cell Biol. 6, 542–554 (2005).

    Article  CAS  Google Scholar 

  46. Pabst, T. et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat. Med. 7, 444–445 (2001).

    Article  CAS  Google Scholar 

  47. Tighe, J.E. & Calabi, F. Alternative, out-of-frame runt/MTG8 transcripts are encoded by the derivative (8) chromosome in the t(8;21) of acute myeloid leukemia M2. Blood 84, 2115–2121 (1994).

    CAS  PubMed  Google Scholar 

  48. van de Locht, L.T., Smetsers, T.F., Wittebol, S., Raymakers, R.A. & Mensink, E.J. Molecular diversity in AML1/ETO fusion transcripts in patients with t(8;21) positive acute myeloid leukaemia. Leukemia 8, 1780–1784 (1994).

    CAS  PubMed  Google Scholar 

  49. Wolford, J.K. & Prochazka, M. Structure and expression of the human MTG8/ETO gene. Gene 212, 103–109 (1998).

    Article  CAS  Google Scholar 

  50. McNeil, S. et al. The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1/CBFalpha2 transcription factor. Proc. Natl. Acad. Sci. USA 96, 14882–14887 (1999).

    Article  CAS  Google Scholar 

  51. Meyers, S. & Hiebert, S.W. Alterations in subnuclear trafficking of nuclear regulatory factors in acute leukemia. J. Cell. Biochem. Suppl. 35, 93–98 (2000).

    Article  Google Scholar 

  52. Laskowski, R.A., Rullmann, J.A.C., MacArthur, M.W., Kaptein, R. & Thornton, J.M. AQUA and PROCHECK_NMR: programs for checking the quality of protein structures solved by NMR. J. Biomol. NMR 8, 477–486 (1996).

    Article  CAS  Google Scholar 

  53. Hooft, R.W.W., Vriend, G., Sander, C. & Abola, E.E. Errors in protein structures. Nature 381, 272 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a fellowship from the Deutsche Forschungsgemeinschaft (LA 1389/1-1 to J.L.), by the Specialized Center of Research Grant from the Leukemia and Lymphoma Society (to M.H.W.) and by the RIKEN Structural Genomics/Proteomics Initiative, the National Project on Protein Structural and Functional Analyses, Ministry of Education, Culture, Sports, Science and Technology of Japan. M.H.W. is a Distinguished Young Scholar of the W.M. Keck Foundation. We thank S. Hiebert (Vanderbilt University), N. Timchenko (Baylor College of Medicine), E.P. Reddy (Temple University), M.J. Klemsz (Indiana University) and S. Nimer (Memorial Sloan-Kettering Cancer Center) for providing expression and reporter vectors, T. Berg and M. Lübbert (University of Freiberg) for sharing AML1-ETO microarray data before publication and M. Punta and B. Rost for sequence analysis of the N-CoR– and E-protein–binding motifs.

Author information

Author notes

  1. Shaohua Liu and Jörn Lausen: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Yufeng Wei, Shaohua Liu, Jörn Lausen, Christopher Woodrell, Seongeun Cho, Nikolaos Biris, Yu Wei & Milton H Werner

  2. RIKEN Genomic Sciences Center, Tsurumi-ku, Yokohama, Kanagawa, Japan

    Naohiro Kobayashi & Shigeyuki Yokoyama

  3. The University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Shigeyuki Yokoyama

Authors
  1. Yufeng Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaohua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jörn Lausen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher Woodrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seongeun Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nikolaos Biris
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naohiro Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shigeyuki Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Milton H Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.W., S.C. and M.H.W. performed the majority of the NMR chemical shift analyses and structure calculations. Protein preparation work was carried out by C.W., Y.W. and M.H.W. S.L. and J.L. performed all of the biological assays. N.B. contributed to the NMR data analysis and computed the ETO-TAFH complex models. N.K. and S.Y. developed the KUJIRA NMR analysis toolkit.

Corresponding author

Correspondence to Milton H Werner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Comparison of 2H7B and ETO-TAFH structures and their per-residue solvent accessibilities. (PDF 414 kb)

Supplementary Fig. 2

Quality assessment for structures of ETO-TAFH. (PDF 1106 kb)

Supplementary Fig. 3

1H-15N HSQC spectra of ETO-TAFH and ETO-TAFH F136Y. (PDF 683 kb)

Supplementary Fig. 4

HADDOCK modeling of the 2H7B complex with a peptide from HEB-AD1. (PDF 516 kb)

Supplementary Data (PDF 131 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wei, Y., Liu, S., Lausen, J. et al. A TAF4-homology domain from the corepressor ETO is a docking platform for positive and negative regulators of transcription. Nat Struct Mol Biol 14, 653–661 (2007). https://doi.org/10.1038/nsmb1258

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb1258

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