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Regulatory intramolecular association in a tyrosine kinase of the Tec family

Nature volume 385, pages 93–97 (1997)Cite this article

Abstract

THE T-cell-specific tyrosine kinase Itk is a member of the Tec family of non-receptor tyrosine kinases1–7, and is required for signalling through the T-cell antigen receptor (TCR)8.The role of Itk in TCR signalling and the manner in which Itk activity is regulated are not well understood. Substrate binding and enzymatic activity of the structurally related Src kinases are regulated by an intramolecular interaction between the Src-homology-2 (SH2) domain and a phosphotyrosine9,10. Although Itk also contains SH3, SH2 and tyrosine kinase domains, it lacks the corresponding regulatory phosphorylation site, and therefore must be regulated by an alternative mechanism. The proline-rich sequence adjacent to the SH3 domain of Tec family kinases contains an SH3 ligand, potentially allowing a different intramolecular interaction. By using multidimensional nuclear magnetic resonance we have determined the structure of a fragment of Itk, confirming that these domains interact intramolecularly. Formation of this intramolecular SH3–ligand complex prevents the Itk SH3 domain and proline-rich region from interacting with their respective protein ligands, Sam68 and Grb-2. We believe that this structure represents the first example of an intramolecular interaction between an SH3 domain and a proline-rich ligand, and has implications for the regulation of Tec family kinases.

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References

  1. Heyeck, S. D. & Berg, L. J. Proc. Natl Acad. Sci. USA 90, 669–673 (1993).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  2. Siliciano, J. D., Morrow, T. A. & Desiderio, S. V. Proc. Natl Acad. Sci. USA 89,11194–11198 (1992).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tanaka, N., Asao, H., Ohtani, K., Nakamura, M. & Sugmua, K. FEBS Lett. 324,1–5 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Mano, H. et al. Oncogene 8, 417–424 (1993).

    CAS  PubMed  Google Scholar 

  5. Tsukada, S. et al. Cell 72, 279–290 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Vetrie, D. et al. Nature 361, 226–232 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Tamagnone, L. et al. Oncogene 9, 3683–3688 (1994).

    CAS  PubMed  Google Scholar 

  8. Liao, X. C. & Littman, D. R. Immunity 3, 757–769 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Courtneidge, S. A. EMBO J. 4, 1471–1477 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cooper, J. A. & Howell, B. Cell 73, 1051–1054 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Chen, J. K., Lane, W. S., Brauer, A. W., Tanaka, A. & Schreiber, S. L. J. Am. Chem. Soc. 115, 12591–12592 (1993).

    Article  CAS  Google Scholar 

  12. Rickles, R. J. et al. Proc. Natl Acad. Sci. USA 92, 10909–10913 (1995).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yu, H. et al. Cell 76, 933–945 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Feng, S., Chen, J. K., Yu, H., Simon, J. A. & Schreiber, S. L. Science 266,1241–1247 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  15. Feng, S., Kasahara, C., Rickles, R. J. & Schreiber, S. L. Proc. Natl Acad. Sci. USA 92, 12408–12415 (1995).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bunnell, S. C. et al. J. Biol. Chem. 271, 25646–25656 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Cheng, G., Ye, Z. & Baltimore, D. Proc. Natl Acad. Sci. USA 91, 8152–8155 (1994).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ikura, M. et al. Science 256, 632–638 (1992).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Marion, D. et al. Biochemistry 28, 6150–6156 (1989).

    Article  CAS  PubMed  Google Scholar 

  20. Zuiderweg, E. R. P. & Fesik, S. W. Biochemistry 28, 2387–2391 (1989).

    Article  CAS  PubMed  Google Scholar 

  21. Chen, J. K. & Schreiber, S. L. Bioorg. Med. Chem. Lett. 4,1755–1760 (1994).

    Article  CAS  Google Scholar 

  22. Anafi, M., Rosen, M. K., Gish, G. D., Kay, L E. & Pawson, T. J. Biol. Chem. 271,21365–21374 (1996).

    Article  CAS  Google Scholar 

  23. Park, H. et al. Immunity 4, 515–525 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Crews, C. M., Alessandrini, A. & Erikson, R. L. Cell Growth Differ. 3, 135–142 (1992).

    CAS  PubMed  Google Scholar 

  25. Pinna, L. A. Biochim. Biophys. Acta 1054, 267–284 (1990).

    Article  CAS  PubMed  Google Scholar 

  26. Woodget, J. R., Gould, K. L. & Hunter, T. Eur. J. Biochem. 161,177–184 (1986).

    Article  Google Scholar 

  27. Rosen, M. K. et al. Nature 374, 477–479 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  28. Brinkmann, U., Mattes, R. E. & Buckel, P. Gene 85, 109–114 (1989).

    Article  CAS  PubMed  Google Scholar 

  29. Brunger, A. T. X-PLOR 3.1 (Yale Univ. Press, New Haven, CT, 1992).

    Google Scholar 

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

    Article  Google Scholar 

Download references

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts, 02138, USA

    Amy Hamilton Andreotti, Sibo Feng & Stuart L. Schreiber

  2. Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts, 02138, USA

    Stephen C. Bunnell & Leslie J. Berg

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  1. Amy Hamilton Andreotti
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Andreotti, A., Bunnell, S., Feng, S. et al. Regulatory intramolecular association in a tyrosine kinase of the Tec family. Nature 385, 93–97 (1997). https://doi.org/10.1038/385093a0

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