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.

A dimerization motif for transmembrane α–helices

Nature Structural Biology volume 1, pages 157–163 (1994)Cite this article

Abstract

Specific helix–helix interactions inside lipid bilayers guide the folding and assembly of many integral membrane proteins and their complexes. We report here a pattern of 7 amino acids (LIxxGVxxGVxxT) which when introduced into several hydrophobic transmembrane α–helices promotes their specific dimerization. Dimerization is driven by interactions that are specific, dominated by the helix–helix interface, and involve no potentially ionizable groups. The motif may provide a useful tool for the functional analysis of such interactions in a variety of systems. Further, since this particular motif is rare, whilst specific helix association is not, many other such motifs may exist, which could permit sorting within complex membranes as well as guiding folding and oligomerization.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

References

  1. Lemmon, M.A. & Engelman, D.M. Helix-helix interactions inside lipid bilayers. Curr. Op. struct. Biol. 2, 511–518 (1992).

    Article  CAS  Google Scholar 

  2. Bormann, B.-J. & Engelman, D.M. Intramembrane helix association in oligomerization and transmembrane signalling. A. Rev. Biophys. biomolec. Struct. 21, 223–242 (1992).

    Article  CAS  Google Scholar 

  3. Popot, J.-L. & Engelman, D.M. Membrane protein folding and oligomerization: The two-stage model. Biochemistry 29, 4031–1037 (1990).

    Article  CAS  Google Scholar 

  4. Popot, J.-L. Integral membrane protein structure: Transmembrane α-helices as autonomous folding domains. Curr. Op. struct. Biol. 3, 532–540 (1993).

    Article  CAS  Google Scholar 

  5. Lemmon, M.A. & Engelman, D.M. Specificity and promiscuity in membrane helix interactions. Quart. Rev. Biophys. (in the press, 1994).

    Google Scholar 

  6. Henderson, R. et al. Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J. molec. Biol. 213, 899–929 (1990).

    Article  CAS  Google Scholar 

  7. Popot, J.-L., Gerchman, S.E. & Engelman, D.M. Refolding of bacteriorhodopsin in lipid bilayers: A thermodynamically controlled two-stage process. J. molec. Biol. 198, 655–676 (1987).

    Article  CAS  Google Scholar 

  8. Kahn, T.W. & Engelman, D.M. Bacteriorhodopsin can be refolded from two independently stable transmembrane helices and the complementary five-helix fragment. Biochemistry 31, 6144–6151 (1992).

    Article  CAS  Google Scholar 

  9. Cosson, P., Lankford, S.P., Bonifacino, J.S. & Klausner, R.D. Membrane protein association by potential intramembrane charge pairs. Nature 351, 414–416 (1991).

    Article  CAS  Google Scholar 

  10. Manolios, N., Bonifacino, J.S. & Klausner, R.D. Transmembrane helical interactions and the assembly of the T-cell receptor complex. Science 249, 274–277 (1990).

    Article  CAS  Google Scholar 

  11. Kurosaki, T., Gander, I. & Ravetch, J.V. (1991). A subunit common to an IgG Fc receptor and the T-cell receptor mediates assembly through different interactions. Proc. natn. Acad. Sci. U.S.A. 88, 3837–3841 (1991).

    Article  CAS  Google Scholar 

  12. Cosson, P. & Bonifacino, J.S. Role of transmembrane domain interactions in the assembly of class II MHC molecules. Science 258, 659–662 (1992).

    Article  CAS  Google Scholar 

  13. Hendrickson, W.A. Modes of transduction. Curr. Biol. 2, 57–59 (1992).

    Article  CAS  Google Scholar 

  14. Cao, H., Bangalore, L., Bormann, B.-J. & Stern, D.F. A subdomain in the transmembrane domain is necessary for p185neu* activation. EMBO J. 11, 923–932 (1992).

    Article  CAS  Google Scholar 

  15. Weiner, D.B., Liu, J., Cohen, J.A., Williams, W.V. & Green, M.I. A point mutation in the neu oncogene mimics ligand induction of receptor aggregation. Nature 339, 230–231 (1989).

    Article  CAS  Google Scholar 

  16. Schlessinger, J. & Ullrich, A. Growth factor signalling by receptor tyrosine kinases. Neuron 9, 383–391 (1992).

    Article  CAS  Google Scholar 

  17. Nilsson, T., Slusarewicz, P., Hoe, M.H. & Warren, G. Kin recognition: A model for the retention of Golgi enzymes. FEBS Lett. 330, 1–4 (1993).

    Article  CAS  Google Scholar 

  18. Weisz, O.A., Swift, A.M. & Machamer, C.E. Oligomerization of a membrane protein correlates with its retention in the Golgi complex. J. Cell Biol. 122, 1185–1196 (1993).

    Article  CAS  Google Scholar 

  19. Smith, S. & Blobel, G. The first membrane spanning region of the lamin B receptor is sufficient for sorting to the inner nuclear membrane. J. Cell Biol. 120, 631–637 (1993).

    Article  CAS  Google Scholar 

  20. Wozniak, R.W. & Blobel, G. The single transmembrane segment of gp210 is sufficient for sorting to the pore membrane domain of the nuclear envelope. J. Cell Biol. 119. 1441–1449 (1992).

    Article  CAS  Google Scholar 

  21. Lemmon, M.A. et al. Glycophorin A dimerization is driven by specific interactions between transmembrane α-helices. J. biol. Chem. 267, 7683–7689 (1992).

    CAS  PubMed  Google Scholar 

  22. Lemmon, M.A., Flanagan, J.M., Treutlein, H.R., Zhang, J. & Engelman, D.M. Sequence-specific dimerization of transmembrane 〈-helices. Biochemistry 31, 12719–12725 (1992).

    Article  CAS  Google Scholar 

  23. Treutlein, H.R., Lemmon, M.A., Engelman, D.M. & Brünger, A.T. The glycophorin A transmembrane domain dimer: Sequence-specific propensity for a right-handed supercoil of helices. Biochemistry 31, 12726–12732 (1992).

    Article  CAS  Google Scholar 

  24. Bormann, B.-J., Knowles, W.J. & Marchesi, V.T. Synthetic peptides mimic the assembly of transmembrane glycoproteins. J. biol. Chem. 264, 4033–4037 (1989).

    CAS  PubMed  Google Scholar 

  25. Pakula, A.A. & Simon, M.I. Determination of transmembrane protein structure by disulfide cross-linking: The Escherichia coli Tar receptor. Proc natn. Acad. Sci. U.S.A. 89, 4144–4148 (1992).

    Article  CAS  Google Scholar 

  26. Whitley, P., Nilsson, L. & von Heijne, G. Three-dimensional model for the membrane domain of Escherichia coli leader peptidase based on disulfide mapping. Biochemistry 32, 8534–8539 (1993).

    Article  CAS  Google Scholar 

  27. Deber, C.M., Khan, A.R., Li, Z., Joensson, C., Glibowicka, M. & Wang, J. Val to Ala mutations selectively alter helix-helix packing in the transmembrane segment of phage M13 coat protein. Proc. natn. Acad. Sci. U.S.A. 90, 11648–11652 (1993).

    Article  CAS  Google Scholar 

  28. Furthmayr, H. & Marchesi, V.T. Subunit structure of human erythrocyte glycophorin A. Biochemistry 15, 1137–1144 (1976).

    Article  CAS  Google Scholar 

  29. Bargmann, C.I., Hung, M.-C. & Weinberg, R.A. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell 45, 649–647 (1986).

    Article  CAS  Google Scholar 

  30. Cao, H., Bangalore, L., Dompé, C., Bormann, B.-J. & Stern, D.F. An extra cysteine proximal to the transmembrane domain induces differential cross-linking of p185neu and p185neu*. J. biol. Chem. 267, 20489–20492 (1992).

    Google Scholar 

  31. Sternberg, M.J.E. & Gullick, W.J. A sequence motif in the transmembrane region of growth factor receptors with tyrosine kinase activity mediates dimerization. Protein Eng. 3, 245–248 (1990).

    Article  CAS  Google Scholar 

  32. Wides, R.J., Zak, N.B. & Shilo, B.-Z. Enhancement of tyrosine kinase activity of the Drosophila epidermal growth factor homolog by alterations of the transmembrane domain. Eur. J. Biochem. 189, 637–645 (1990).

    Article  CAS  Google Scholar 

  33. Frattali, A.L., Treadway, J.L. & Pessin, J.E. Evidence supporting a passive role for the insulin receptor transmembrane domain in insulin-dependent signal transduction. J. biol. Chem. 266, 9829–9834 (1991).

    CAS  PubMed  Google Scholar 

  34. Longo, N., Shuster, R.C., Griffin, L.R., Langley, S.D. & Elsas, L.J. Activation of insulin receptor signaling by a single amino-acid substitution in the transmembrane domain. J. biol. Chem. 267, 12416–12419 (1992).

    CAS  PubMed  Google Scholar 

  35. Yamada, K., Goncalves, E., Kahn, C.R. & Shoelson, S.E. Substitution of the insulin receptor transmembrane domain with the c-neu/erbB2 transmembrane domain constitutively activates the insulin receptor in vitro. J. biol. Chem. 267, 12452–12461 (1992).

    CAS  PubMed  Google Scholar 

  36. Cheatham, B., Shoelson, S.E., Yamada, K., Goncalves, E. & Kahn, C.R. Substitution of the erbB-2 oncoprotein transmembrane domain activates the insulin receptor and modulates the action of insulin and insulin-receptor substrate 1. Proc. natn. Acad. Sci. U.S.A. 90, 7336–7340 (1993).

    Article  CAS  Google Scholar 

  37. Carpenter, C.D. et al. Structural analysis of the transmembrane domain of the epidermal growth factor receptor. J. biol. Chem. 266, 5750–5755 (1991).

    CAS  PubMed  Google Scholar 

  38. Kashles, O. et al. Ligand-induced stimulation of epidermal growth factor receptor mutants with altered transmembrane regions. Proc. natn. Acad. Sci. U.S.A. 85, 9567–9571 (1988).

    Article  CAS  Google Scholar 

  39. Adair, B.D. An investigation into the effects of packing on the folding of integral membrane proteins. Ph.D. Thesis, Yale University, New Haven, CT, U.S.A. (1993).

    Google Scholar 

  40. Lee, A.W. & Nienhuis, A.W. Functional dissection of structural domains in the receptor for colony-stimulating factor-1. J. biol. Chem. 267, 16472–16483 (1992).

    CAS  PubMed  Google Scholar 

  41. Devereux, J., Haeberli, P. & Smithies, O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 12, 387–395 (1984).

    Article  CAS  Google Scholar 

  42. Higuchi, R. Recombitant PCR. in PCR protocols, a guide to methods and applications (eds Innis, M.A. et al.) 177–183 (Academic Press, San Diego, 1990)

    Google Scholar 

Download references

Author information

Author notes

  1. Mark A. Lemmon

    Present address: Department of Pharmacology, New York University Medical Center, 550 First Avenue, New York, NY, 10016, USA

  2. Herbert R. Treutlein

    Present address: Ludwig Institute for Cancer Research, P.O. Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia

Authors and Affiliations

  1. Department of Molecular Biophysics & Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT, 06520, USA

    Mark A. Lemmon, Herbert R. Treutlein, Paul D. Adams, Axel T. Brünger & Donald M. Engelman

  2. Howard Hughes Medical Institute, Yale University, 266 Whitney Avenue, New Haven, CT, 06520, USA

    Herbert R. Treutlein & Axel T. Brünger

Authors
  1. Mark A. Lemmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Herbert R. Treutlein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul D. Adams
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Axel T. Brünger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donald M. Engelman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lemmon, M., Treutlein, H., Adams, P. et al. A dimerization motif for transmembrane α–helices. Nat Struct Mol Biol 1, 157–163 (1994). https://doi.org/10.1038/nsb0394-157

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsb0394-157

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