Structural Reorganization of the Toll-Like Receptor 8 Dimer Induced by Agonistic Ligands

Tanji, Hiromi; Ohto, Umeharu; Shibata, Takuma; Miyake, Kensuke; Shimizu, Toshiyuki

doi:10.1126/science.1229159

Cited by 297 publications

(399 citation statements)

References 39 publications

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“…The preformed Toll dimer appears to represent an inactive state of the receptor, similar to the situation described recently for the unliganded TLR8 (20), kept in place by stabilizing interactions between their juxtaposing N-terminal domains. We suggest that binding of Spätzle disrupts this complex, leading to a rearrangement of the dimer that allows a close approach of the C-terminal membrane proximal domains to initiate Toll signaling (SI Appendix, Figs.…”

Section: Discussionsupporting

confidence: 67%

“…Although it is well established that weak protein-protein interactions in solution can be enhanced considerably on 2D confinement within a membrane (47) [e.g., the 2:2 TLR5:Flic dimer responsible for flagellin recognition was not detectable using gel filtration and revealed a K d of only ∼5 mM using analytical ultracentrifugation (21)], all TLR-agonist complexes studied to date show dimer formation at the high protein concentrations prevalent during crystallization (18)(19)(20)(21). Although it is possible that the 1:1 Toll-Spätzle dimer observed here may represent a presignaling complex, the situation is reminiscent of the TLR4-MD2 complex, in which initial elucidation of the structure revealed a monomeric complex (38).…”

Section: Discussionmentioning

confidence: 99%

“…The mammalian TLRs are activated directly by bacterial, fungal, or viral components known as pathogen-associated molecular patterns (17), and representative structures of seven ectodomains (ECDs) of the 11 known mammalian TLRs (TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, and TLR8) are available (18)(19)(20)(21). Common to all of these receptors is ligand-induced activation via homodimer or heterodimer formation, although the specifics of this process can vary considerably.…”

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confidence: 99%

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Structure of the Toll-Spätzle complex, a molecular hub in Drosophila development and innate immunity

Parthier¹,

Stelter²,

Ursel³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Drosophila Toll receptors are involved in embryonic development and the immune response of adult flies. In both processes, the only known Toll receptor ligand is the human nerve growth factor-like cystine knot protein Spätzle. Here we present the crystal structure of a 1:1 (nonsignaling) complex of the full-length Toll receptor ectodomain (ECD) with the Spätzle cystine knot domain dimer. The ECD is divided into two leucine-rich repeat (LRR) domains, each of which is capped by cysteine-rich domains. Spätzle binds to the concave surface of the membrane-distal LRR domain, in contrast to the flanking ligand interactions observed for mammalian Toll-like receptors, with asymmetric contributions from each Spätzle protomer. The structure allows rationalization of existing genetic and biochemical data and provides a framework for targeting the immune systems of insects of economic importance, as well as a variety of invertebrate disease vectors.Toll signaling | embryonic morphogenesis | protein evolution T he model organism Drosophila melanogaster has yielded valuable insights into a number of fundamental biological processes. Genetic screens of flies subjected to chemical saturation mutagenesis have revealed a host of genes necessary for development, including Toll (from the German for "fantastic"), identified as a major determinant in the development of dorsalventral polarity (1-3). Toll encodes for a type I integral membrane protein with a large N-terminal extracellular domain consisting of a series of leucine-rich repeats (LRRs) (4) flanked by cysteine-rich motifs (5). The cytoplasmic intracellular C-terminal domain shares significant similarities with the mammalian interleukin-1 receptor (6, 7) and thus is termed the Toll-interleukin receptor (TIR) domain.Microinjection experiments have identified the spz gene product Spätzle as the ligand for Toll (8, 9). The morphogen, present throughout the perivitelline space in the form of an inactive precursor proSpätzle, undergoes activation cleavage by the serine protease Easter (10) (itself activated during development by a spatially confined proteolytic cascade), leading to an extracellular gradient of activated Spätzle in the developing embryo (reviewed in ref. 11). Spätzle-mediated activation of the Toll receptor results in nuclear localization of the NF-κB/rel transcription factor Dorsal (12), eliciting transcription of further ventral-specific differentiation genes. In addition, the absence of nuclear Dorsal protein on the dorsal side of the embryo derepresses another distinct class of genes (13).

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Structure of the Toll-Spätzle complex, a molecular hub in Drosophila development and innate immunity

Parthier¹,

Stelter²,

Ursel³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…5). Recently, the structure of human TLR8 with its ligand was solved, and the ligand-binding domains and dimerization interfaces were identified 23 . The anti-TLR7 mAb epitope is close to the TLR7 regions corresponding to the two ligandbinding sites and one dimerization interface of TLR8: 263Y and 351-356 for ligand-binding and 264-268 for dimerization.…”

Section: Anti-tlr7mentioning

confidence: 99%

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

et al. 2015

Self Cite

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Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can also potentially respond to self-derived RNA. To prevent autoimmune responses, TLR7 is thought to localize in endolysosomes. Contrary to this view, we show here that TLR7 is present on the cell surface of immune cells and that TLR7 responses can be inhibited by an anti-TLR7 antibody. The anti-TLR7 antibody is internalized with TLR7 and accumulates in endolysosomes as an immune complex. TLR7 responses in dendritic cells, macrophages and B cells are all inhibited by the anti-TLR7 antibody. Furthermore, the anti-TLR7 antibody inhibits in vivo cytokine production induced by a TLR7 ligand. Spontaneous TLR7 activation in Unc93b1 D34A/D34A mice causes lethal inflammation. Progressive inflammation such as splenomegaly, thrombocytopenia and chronic active hepatitis are ameliorated by anti-TLR7 antibody treatment. These results demonstrate that cell surface TLR7 is a promising target for therapeutic intervention in autoimmune diseases.

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“…TLR5 is stimulated by flagellin, a protein involved in motility in many bacteria. In contrast, TLR3, 7, 8 and 9 are activated by viral pathogenic molecules [13][14][15][16], namely: TLR3, double stranded RNA [17] associated with many viruses; TLR7 and 8, single stranded RNA present in viruses such as Ebola [14][15][16]18]; TLR9, CpG-rich DNA, a form of DNA prevalent in viral and bacterial genomes [19].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

The role of protein–protein interactions in Toll-like receptor function

Berglund

Kargas

Ortiz-Suarez

et al. 2015

Progress in Biophysics and Molecular Biology

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As part of the innate immune system, the Toll-like receptors (TLRs) represent key players in the first line of defense against invading foreign pathogens, and are also major targets for therapeutic immunomodulation. TLRs are type I transmembrane proteins composed of an ectodomain responsible for ligand binding, a single-pass transmembrane domain, and a cytoplasmic Toll/Interleukin-1 receptor (TIR) signaling domain. The ectodomains of TLRs are specialized for recognizing a wide variety of pathogen-associated molecular patterns, ranging from lipids and lipopeptides to proteins and nucleic acid fragments. The members of the TLR family are highly conserved and their ectodomains are composed of characteristic, solenoidal leucine-rich repeats (LRRs). Upon ligand binding, these rigid LRR scaffolds dimerize (or re-organize in the case of pre-formed dimers) to bring together their carboxy-terminal transmembrane and TIR domains. The latter are proposed to act as a platform for recruitment of adaptor proteins and formation of higher-order complexes, resulting in propagation of downstream signaling cascades. In this review, we discuss the protein-protein interactions critical for formation and stability of productive, ligand-bound TLR complexes. In particular, we focus on the large body of high-resolution crystallographic data now available for the ectodomains of homo-and heterodimeric TLR complexes, as well as inhibitory TLR-like receptors, and also consider computational approaches that can facilitate our understanding of the ligand-induced conformational changes associated with TLR function. We also briefly consider what is known about the protein-protein interactions involved in both TLR transmembrane domain assembly and TIRmediated signaling complex formation in light of recent structural and biochemical data.

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Structural Reorganization of the Toll-Like Receptor 8 Dimer Induced by Agonistic Ligands

Cited by 297 publications

References 39 publications

Structure of the Toll-Spätzle complex, a molecular hub in Drosophila development and innate immunity

Structure of the Toll-Spätzle complex, a molecular hub in Drosophila development and innate immunity

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

The role of protein–protein interactions in Toll-like receptor function

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