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TLRs bent into shape

Nature Immunology volume 8, pages 675–677 (2007)Cite this article

Toll-like receptors respond to ligands embedded in pathogen-derived macromolecules to induce immune responses. Binding of a stimulatory ligand to preexisting dimers of Toll-like receptor 9 induces conformational changes that lead to their full activation.

The body senses the presence of a diverse array of pathogen-associated molecules by means of Toll-like receptors (TLRs)1. Engagement of TLRs not only induces the expression of antimicrobial genes and inflammatory cytokines but also contributes to adaptive immunity through the activation of dendritic cells and B cells. TLRs are type I membrane proteins composed of a large ectodomain, a single transmembrane domain and a cytoplasmic Toll–interleukin 1 receptor (TIR) domain. TLR ectodomains contain 18–25 tandem copies of a leucine-rich repeat motif and are responsible for the recognition of a wide range of pathogen-derived macromolecules and small synthetic compounds (such as imidazoquinolines). How the various TLRs exercise their ligand specificity is not known; except for TLR9, direct binding of TLR agonists to purified TLRs remains to be demonstrated. Moreover, how engagement of TLRs transmits information across the plasma membrane to activate intracellular signal cascades is equally unclear. In this issue of Nature Immunology, Latz et al. show that TLR9, which recognizes unmethylated CpG-containing DNA sequences ('CpG DNA'), exists as a constitutive dimer and, after binding stimulatory CpG DNA, undergoes conformational changes in its ectodomain that bring the two cytoplasmic TIR domains in the dimer together2. This ligand-induced arrangement provides a plausible mechanism for TLR activation through repositioning of the cytoplasmic tails, followed by the recruitment of 'downstream' cytoplasmic effectors to a newly created dimer interface.

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Figure 1: Binding of CpG DNA induces conformational changes in TLR9.

References

  1. Takeda, K., Kaisho, T. & Akira, S. Annu. Rev. Immunol. 21, 335–376 (2003).

    CAS  Article  Google Scholar 

  2. Latz, E. et al. Nat. Immunol. 8, 772–779 (2007).

    CAS  Article  Google Scholar 

  3. Weber, A.N. et al. Nat. Immunol. 4, 794–800 (2003).

    CAS  Article  Google Scholar 

  4. Kobayashi, M. et al. J. Immunol. 176, 6211–6218 (2006).

    CAS  Article  Google Scholar 

  5. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C.A., Jr. Nature 388, 394–397 (1997).

    CAS  Article  Google Scholar 

  6. Ozinsky, A. et al. Proc. Natl. Acad. Sci. USA 97, 13766–13771 (2000).

    CAS  Article  Google Scholar 

  7. Choe, J., Kelker, M.S. & Wilson, I.A. Science 309, 581–585 (2005).

    CAS  Article  Google Scholar 

  8. Latz, E. et al. Nat. Immunol. 5, 190–198 (2004).

    CAS  Article  Google Scholar 

  9. Bell, J.K. et al. Proc. Natl. Acad. Sci. USA 102, 10976–10980 (2005).

    CAS  Article  Google Scholar 

  10. Ahmad-Nejad, P. et al. Eur. J. Immunol. 32, 1958–1968 (2002).

    CAS  Article  Google Scholar 

  11. Brinkmann, M.M. et al. J. Cell Biol. 177, 265–275 (2007).

    CAS  Article  Google Scholar 

  12. Tabeta, K. et al. Nat. Immunol. 7, 156–164 (2007).

    Article  Google Scholar 

  13. Spooner, R.A., Smith, D.C., Easton, A.J., Roberts, L.M. & Lord, J.M. J. Virol. 3, 26 (2006).

    Article  Google Scholar 

Download references

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  1. You-Me Kim, Melanie M. Brinkmann and Hidde L. Ploegh are with the Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology Boston, Massachusetts 02142, USA. ploegh@wi.mit.edu

    You-Me Kim, Melanie M Brinkmann & Hidde L Ploegh

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  1. You-Me Kim
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  2. Melanie M Brinkmann
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  3. Hidde L Ploegh
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Kim, YM., Brinkmann, M. & Ploegh, H. TLRs bent into shape. Nat Immunol 8, 675–677 (2007). https://doi.org/10.1038/ni0707-675

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