The Structural Biology of Toll-like Receptors

Overview

Journal Structure

Publisher Cell Press

Specialties Biochemistry
Biotechnology
Cell Biology
Molecular Biology

Date 2011 Apr 13

PMID 21481769

Citations 295

Authors

Istvan Botos

David M Segal

David R Davies

Affiliations

Soon will be listed here.

Abstract

The membrane-bound Toll-like receptors (TLRs) trigger innate immune responses after recognition of a wide variety of pathogen-derived compounds. Despite the wide range of ligands recognized by TLRs, the receptors share a common structural framework in their extracellular, ligand-binding domains. These domains all adopt horseshoe-shaped structures built from leucine-rich repeat motifs. Typically, on ligand binding, two extracellular domains form an "m"-shaped dimer sandwiching the ligand molecule bringing the transmembrane and cytoplasmic domains in close proximity and triggering a downstream signaling cascade. Although the ligand-induced dimerization of these receptors has many common features, the nature of the interactions of the TLR extracellular domains with their ligands varies markedly between TLR paralogs.

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References

He X, Bazan J, McDermott G, Park J, Wang K, Tessier-Lavigne M . Structure of the Nogo receptor ectodomain: a recognition module implicated in myelin inhibition. Neuron. 2003; 38(2):177-85. DOI: 10.1016/s0896-6273(03)00232-0. View

Han B, Herrin B, Cooper M, Wilson I . Antigen recognition by variable lymphocyte receptors. Science. 2008; 321(5897):1834-7. PMC: 2581502. DOI: 10.1126/science.1162484. View

Huizinga E, Tsuji S, Romijn R, Schiphorst M, de Groot P, Sixma J . Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science. 2002; 297(5584):1176-9. DOI: 10.1126/science.107355. View

Janeway Jr C, Medzhitov R . Innate immune recognition. Annu Rev Immunol. 2002; 20:197-216. DOI: 10.1146/annurev.immunol.20.083001.084359. View

Peter M, Kubarenko A, Weber A, Dalpke A . Identification of an N-terminal recognition site in TLR9 that contributes to CpG-DNA-mediated receptor activation. J Immunol. 2009; 182(12):7690-7. DOI: 10.4049/jimmunol.0900819. View

Park B, Brinkmann M, Spooner E, Lee C, Kim Y, Ploegh H . Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol. 2008; 9(12):1407-14. PMC: 2735466. DOI: 10.1038/ni.1669. View

Divanovic S, Trompette A, Petiniot L, Allen J, Flick L, Belkaid Y . Regulation of TLR4 signaling and the host interface with pathogens and danger: the role of RP105. J Leukoc Biol. 2007; 82(2):265-71. DOI: 10.1189/jlb.0107021. View

Khan J, Brint E, ONeill L, Tong L . Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL. J Biol Chem. 2004; 279(30):31664-70. DOI: 10.1074/jbc.M403434200. View

Beutler B, Rietschel E . Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol. 2003; 3(2):169-76. DOI: 10.1038/nri1004. View

10.

Park H, Logette E, Raunser S, Cuenin S, Walz T, Tschopp J . Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell. 2007; 128(3):533-46. PMC: 2908332. DOI: 10.1016/j.cell.2007.01.019. View

11.

Gay N, Gangloff M, ONeill L . What the Myddosome structure tells us about the initiation of innate immunity. Trends Immunol. 2011; 32(3):104-9. DOI: 10.1016/j.it.2010.12.005. View

12.

Vijay-Kumar M, Aitken J, Carvalho F, Cullender T, Mwangi S, Srinivasan S . Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science. 2010; 328(5975):228-31. PMC: 4714868. DOI: 10.1126/science.1179721. View

13.

Omueti K, Mazur D, Thompson K, Lyle E, Tapping R . The polymorphism P315L of human toll-like receptor 1 impairs innate immune sensing of microbial cell wall components. J Immunol. 2007; 178(10):6387-94. DOI: 10.4049/jimmunol.178.10.6387. View

14.

Han S, Kim J, Martin M, Michalek S, Nahm M . Pneumococcal lipoteichoic acid (LTA) is not as potent as staphylococcal LTA in stimulating Toll-like receptor 2. Infect Immun. 2003; 71(10):5541-8. PMC: 201083. DOI: 10.1128/IAI.71.10.5541-5548.2003. View

15.

Dunne A, Ejdeback M, Ludidi P, ONeill L, Gay N . Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88. J Biol Chem. 2003; 278(42):41443-51. DOI: 10.1074/jbc.M301742200. View

16.

Jin M, Kim S, Heo J, Lee M, Kim H, Paik S . Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell. 2007; 130(6):1071-82. DOI: 10.1016/j.cell.2007.09.008. View

17.

Jung D, Alt F . Unraveling V(D)J recombination; insights into gene regulation. Cell. 2004; 116(2):299-311. DOI: 10.1016/s0092-8674(04)00039-x. View

18.

Andersen-Nissen E, Smith K, Bonneau R, Strong R, Aderem A . A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J Exp Med. 2007; 204(2):393-403. PMC: 2118731. DOI: 10.1084/jem.20061400. View

19.

Kim H, Park B, Kim J, Kim S, Lee J, Oh S . Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell. 2007; 130(5):906-17. DOI: 10.1016/j.cell.2007.08.002. View

20.

Miyake K, Shimazu R, Kondo J, Niki T, Akashi S, Ogata H . Mouse MD-1, a molecule that is physically associated with RP105 and positively regulates its expression. J Immunol. 1998; 161(3):1348-53. View