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Toll-like receptors as molecular switches

Nature Reviews Immunology volume 6, pages 693–698 (2006)Cite this article

Abstract

Members of the Toll family of single-pass transmembrane receptors are key mediators of innate immunity in both vertebrates and invertebrates. They respond to various pathogen-associated stimuli and transduce the complex signalling responses that are required for inflammation and for the subsequent development of adaptive immunity. Here, we propose a molecular mechanism for signalling by the Toll and Toll-like receptors that involves a series of protein conformational changes initiated by dimerization of their extracellular domains. The initial dimerization event, which is triggered by the interaction of the receptor with its ligand, might disrupt a pre-formed but non-functional dimer. Formation of a stable receptor–ligand complex then relieves constitutive autoinhibition, enabling receptor–receptor association of the extracellular juxtamembrane regions and cytoplasmic signalling domains. This activation process constitutes a tightly regulated, unidirectional molecular switch.

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Figure 1: Basic architecture of Toll and Toll-like receptors.
Figure 2: Ligand binding by a leucine-rich-repeat-containing protein.
Figure 3: Toll-like-receptor ectodomain and ligands (stimuli).
Figure 4: Model for Drosophila Toll activation by Spätzle.
Figure 5: Compartmentalization of Toll-like receptors, signalling and termination of signalling.

References

  1. Belvin, M. P. & Anderson, K. V. A conserved signaling pathway: the Drosophila Toll–Dorsal pathway. Annu. Rev. Cell Dev. Biol. 12, 393–416 (1996).

    Article  CAS  Google Scholar 

  2. Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol. 4, 499–511 (2004).

    Article  CAS  Google Scholar 

  3. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987–995 (2004).

    Article  CAS  Google Scholar 

  4. Beutler, B. & Poltorak, A. Sepsis and evolution of the innate immune response. Crit. Care Med. 29, S2–S6; discussion S6–S7 (2001).

    Article  CAS  Google Scholar 

  5. Rock, F. L., Hardiman, G., Timans, J. C., Kastelein, R. A. & Bazan, J. F. A family of human receptors structurally related to Drosophila Toll. Proc. Natl Acad. Sci. USA 95, 588–593 (1998).

    Article  CAS  Google Scholar 

  6. Buchanan, S. G. S. & Gay, N. J. Structural and functional diversity in the leucine rich repeat family of proteins. Prog. Biophys. Mol. Biol. 65, 1–44 (1996).

    Article  CAS  Google Scholar 

  7. Fan, Q. R. & Hendrickson, W. A. Structure of human follicle-stimulating hormone in complex with its receptor. Nature 433, 269–277 (2005).

    Article  CAS  Google Scholar 

  8. Schimmele, B. & Pluckthun, A. Identification of a functional epitope of the Nogo receptor by a combinatorial approach using ribosome display. J. Mol. Biol. 352, 229–241 (2005).

    Article  CAS  Google Scholar 

  9. Alder, M. N. et al. Diversity and function of adaptive immune receptors in a jawless vertebrate. Science 310, 1970–1973 (2005).

    Article  CAS  Google Scholar 

  10. Weber, A. et al. Binding of the Drosophila cytokine Spätzle to Toll is direct and establishes signaling. Nature Immunol. 4, 794–800 (2003).

    Article  CAS  Google Scholar 

  11. Nagai, Y. et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nature Immunol. 3, 667–672 (2002).

    Article  CAS  Google Scholar 

  12. Inohara, N. & Nunez, G. ML – a conserved domain involved in innate immunity and lipid metabolism. Trends Biochem. Sci. 27, 219–221 (2002).

    Article  CAS  Google Scholar 

  13. Gangloff, M. & Gay, N. J. MD-2: the Toll 'gatekeeper' in endotoxin signalling. Trends Biochem. Sci. 29, 294–300 (2004).

    Article  CAS  Google Scholar 

  14. Hailman, E. et al. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J. Exp. Med. 179, 269–277 (1994).

    Article  CAS  Google Scholar 

  15. Weber, A. N., Moncrieffe, M. C., Gangloff, M., Imler, J. L. & Gay, N. J. Ligand–receptor and receptor–receptor interactions act in concert to activate signaling in the Drosophila Toll pathway. J. Biol. Chem. 280, 22793–22799 (2005).

    Article  CAS  Google Scholar 

  16. Winans, K. A. & Hashimoto, C. Ventralization of the Drosophila embryo by deletion of extracellular leucine-rich repeats in the Toll protein. Mol. Biol. Cell 6, 587–596 (1995).

    Article  CAS  Google Scholar 

  17. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr . A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).

    Article  CAS  Google Scholar 

  18. Schneider, D. S., Hudson, K. L., Lin, T. Y. & Anderson, K. V. Dominant and recessive mutations define functional domains of Toll, a transmembrane protein required for dorsal ventral polarity in the Drosophila embryo. Genes Dev. 5, 797–807 (1991).

    Article  CAS  Google Scholar 

  19. Hu, X., Yagi, Y., Tanji, T., Zhou, S. & Ip, Y. T. Multimerization and interaction of Toll and Spätzle in Drosophila. Proc. Natl Acad. Sci. USA 101, 9369–9374 (2004).

    Article  CAS  Google Scholar 

  20. Shimazu, R. et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189, 1777–1782 (1999).

    Article  CAS  Google Scholar 

  21. Matsumoto, M., Kikkawa, S., Kohase, M., Miyake, K. & Seya, T. Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem. Biophys. Res. Commun. 293, 1364–1369 (2002).

    Article  CAS  Google Scholar 

  22. Koshland, D. E. Jr . The structural basis of negative cooperativity: receptors and enzymes. Curr. Opin. Struct. Biol. 6, 757–761 (1996).

    Article  CAS  Google Scholar 

  23. Urizar, E. et al. Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity. EMBO J. 24, 1954–1964 (2005).

    Article  CAS  Google Scholar 

  24. He, X. L. & Garcia, K. C. Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science 304, 870–875 (2004).

    Article  CAS  Google Scholar 

  25. Bell, J. K. et al. The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proc. Natl Acad. Sci. USA 102, 10976–10980 (2005).

    Article  CAS  Google Scholar 

  26. Choe, J., Kelker, M. S. & Wilson, I. A. Crystal structure of human Toll-like receptor 3 (TLR3) ectodomain. Science 309, 581–585 (2005).

    Article  CAS  Google Scholar 

  27. Kirk, P. & Bazan, J. F. Pathogen recognition: TLRs throw us a curve. Immunity 23, 347–350 (2005).

    Article  CAS  Google Scholar 

  28. Bell, J. K., Askins, J., Hall, P. R., Davies, D. R. & Segal, D. M. The dsRNA binding site of human Toll-like receptor 3. Proc. Natl Acad. Sci. USA 103, 8792–8797 (2006).

    Article  CAS  Google Scholar 

  29. O'Neill, L. A. J., Fitzgerald, K. A. & Bowie, A. G. The Toll–IL-1 receptor adaptor family grows to five members. Trends Immunol. 24, 286–290 (2003).

    Article  Google Scholar 

  30. Xu, Y. W. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111–115 (2000).

    Article  CAS  Google Scholar 

  31. Dunne, A., Ejdeback, M., Ludidi, P., O'Neill, L. A. J. & Gay, N. J. Structural complementarity of Toll/interleukin-1 receptor identity regions in Toll-like receptors and the adaptors Mal and MyD88. J. Biol. Chem. 278, 41443–41451 (2003).

    Article  CAS  Google Scholar 

  32. Fitzgerald, K. A. et al. LPS–TLR4 signaling to IRF-3/7 and NF-κB involves the Toll adapters TRAM and TRIF. J. Exp. Med. 198, 1043–1055 (2003).

    Article  CAS  Google Scholar 

  33. Lu, X., Gross, A. W. & Lodish, H. F. Active conformation of the erythropoietin receptor: random and cysteine-scanning mutagenesis of the extracellular juxtamembrane and transmembrane domains. J. Biol. Chem. 281, 7002–7011 (2006).

    Article  CAS  Google Scholar 

  34. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  CAS  Google Scholar 

  35. Tao, X., Xu, Y. W., Zheng, Y., Beg, A. A. & Tong, L. An extensively associated dimer in the structure of the C713S mutant of the TIR domain of human TLR2. Biochem. Biophys. Res. Commun. 299, 216–221 (2002).

    Article  CAS  Google Scholar 

  36. Ronni, T. et al. Common interaction surfaces of the Toll-like receptor 4 cytoplasmic domain stimulate multiple nuclear targets. Mol. Cell. Biol. 23, 2543–2555 (2003).

    Article  CAS  Google Scholar 

  37. Gioannini, T. L. et al. Isolation of an endotoxin–MD-2 complex that produces Toll-like receptor 4-dependent cell activation at picomolar concentrations. Proc. Natl Acad. Sci. USA 101, 4186–4191 (2004).

    Article  CAS  Google Scholar 

  38. Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).

    Article  CAS  Google Scholar 

  39. Bauer, S. et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl Acad. Sci. USA 98, 9237–9242 (2001).

    Article  CAS  Google Scholar 

  40. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).

    Article  CAS  Google Scholar 

  41. Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nature Immunol. 3, 196–200 (2002).

    Article  CAS  Google Scholar 

  42. Bell, J. K. et al. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol. 24, 528–533 (2003).

    Article  CAS  Google Scholar 

  43. Gibbard, R. J., Morley, P. J. & Gay, N. J. Conserved features in the extracellular domain of human Toll-like receptor 8 are essential for pH dependent signalling. J. Biol. Chem. 20 July 2006 (doi:10.1074/jbc.M605003200).

  44. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol. 5, 190–198 (2004).

    Article  CAS  Google Scholar 

  45. Lee, J. et al. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc. Natl Acad. Sci. USA 100, 6646–6651 (2003).

    Article  CAS  Google Scholar 

  46. Barton, G. M., Kagan, J. C. & Medzhitov, R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nature Immunol. 7, 49–56 (2006).

    Article  CAS  Google Scholar 

  47. Husebye, H. et al. Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity. EMBO J. 25, 683–692 (2006).

    Article  CAS  Google Scholar 

  48. Schlessinger, J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 110, 669–672 (2002).

    Article  CAS  Google Scholar 

  49. Cho, H. S. et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421, 756–760 (2003).

    Article  CAS  Google Scholar 

  50. Klosterman, P. S., Shah, S. A. & Steitz, T. A. Crystal structures of two plasmid copy control related RNA duplexes: an 18 base pair duplex at 1.20 Å resolution and a 19 base pair duplex at 1.55 Å resolution. Biochemistry 38, 14784–14792 (1999).

    Article  CAS  Google Scholar 

  51. Mizuguchi, K., Parker, J. S., Blundell, T. L. & Gay, N. J. Getting knotted: a model for the structure and activation of Spätzle. Trends Biochem. Sci. 23, 239–242 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank the Medical Research Council (UK), the Biotechnology and Biological Sciences Research Council (UK) and the Wellcome Trust (UK) for grant support.

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Authors and Affiliations

  1. the Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK

    Nicholas J. Gay & Monique Gangloff

  2. the German Cancer Research Centre (DKFZ), Angewandte Tumorvirologie (ATV), Im Neuenheimer Feld, Heidelberg, 69242, Germany

    Alexander N. R. Weber

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  1. Nicholas J. Gay
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Correspondence to Nicholas J. Gay.

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Gay, N., Gangloff, M. & Weber, A. Toll-like receptors as molecular switches. Nat Rev Immunol 6, 693–698 (2006). https://doi.org/10.1038/nri1916

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