Lateral Clustering of TLR3:dsRNA Signaling Units Revealed by TLR3ecd:3Fabs Quaternary Structure

Luo, Jinquan; Obmolova, Galina; Malia, T.; Wu, Sheng‐Jiun; Duffy, Karen E.; Marion, James; Bell, Jessica K.; Ge, Peng; Zhou, Z.H.; Teplyakov, A.; Zhao, Yong-Qi; Lamb, Roberta J.; Jordan, Jarrat L.; Mateo, Lani R. San; Sweet, Raymond W.; Gilliland, Gary L.

doi:10.1016/j.jmb.2012.05.006

Cited by 40 publications

(35 citation statements)

References 40 publications

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“…The present work proposes a key for future analysis about an IFN-inducing signaling complex in the context of TLR4-mediated LPS signaling. Recent studies showed the importance of lateral TLR3 clustering mediated by TICAM-1 for downstream signaling (36), consistent with our model.…”

Section: Discussionsupporting

confidence: 92%

Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling

Enokizono

Kumeta

Funami

et al. 2013

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

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Homotypic and heterotypic interactions between Toll/interleukin-1 receptor (TIR) domains in Toll-like receptors (TLRs) and downstream adaptors are essential to evoke innate immune responses. However, such oligomerization properties present intrinsic difficulties in structural studies of TIR domains. Here, using BB-loop mutations that disrupt homotypic interactions, we determined the structures of the monomeric TIR domain-containing adaptor molecule (TICAM)-1 and TICAM-2 TIR domains. Docking of the monomeric structures, together with yeast two hybrid-based mutagenesis assays, reveals that the homotypic interaction between TICAM-2 TIR is indispensable to present a scaffold for recruiting the monomeric moiety of the TICAM-1 TIR dimer. This result proposes a unique idea that oligomerization of upstream TIR domains is crucial for binding of downstream TIR domains. Furthermore, the bivalent nature of each TIR domain dimer can generate a large signaling complex under the activated TLRs, which would recruit downstream signaling molecules efficiently. This model is consistent with previous reports that BB-loop mutants completely abrogate downstream signaling. A large number of TIR domain structures, including receptors and adaptors, have been determined by X-ray crystallography and NMR. The receptors include TLR1 (9), TLR2 (10), and IL-1R accessory protein-like (IL-1RAPL) (11). Adaptors include myeloid differentiation factor 88 (MyD88) (12) and MyD88 adaptorlike (Mal) (13,14). In addition, AtTIR (15, 16) derived from Arabidopsis thaliana and PdTIR (17) from bacteria have been solved. Each of these TIR domain structures has a ferredoxin fold with five β-strands (βA-βE), five α-helices (αA-αE), and loops connecting β-strands and α-helices (9). Although homotypic interactions of the TIR domains have been proposed based on the crystal structures, most proposed models have small interacting surfaces, possibly due to crystal contacts. Recently, however, a crystal structure of the TLR10 TIR domain was reported that forms a homotypic dimer mediated by the loop connecting βB and αB (designated "BB-loop") (18). Interestingly, BB-loop mutations in TLR4 were reported to be dominant-negative and abrogated downstream signaling (19). TICAM-1 and TICAM-2 harboring BB-loop mutations are also dominant-negative and unable to form homotypic interactions (1, 2), reinforcing the importance of BB-loop-mediated homotypic dimer formation in signal propagation.Despite extensive structural studies, it is not known why homotypic interactions are essential for downstream signaling (20-27). To address this issue, it is necessary to discriminate residues required for homotypic and those required for heterotypic interactions. Here, we first determine the structures of the monomeric BB-loop mutants of the TICAM-1 and TICAM-2 TIR domains using NMR. Then, based on the solution structures of the BB-loop mutants, coupled mutagenesis/yeast two-hybrid experiments, and restrained docking calculations, we show that the homotypic interaction of TICAM-2 TIR is es...

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Section: Discussionsupporting

confidence: 92%

Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling

Enokizono

Kumeta

Funami

et al. 2013

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

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“…These observations suggest that clustering of more than one TLR3 dimer may be necessary for an adequate immune response. A recent study supports this model . They produced antibodies that can block activity of TLR3.…”

Section: Dimerization and Activation Of Tlrsmentioning

confidence: 77%

“…B ). This kind of higher order clustering of receptor multimers has been proposed for quite a few membrane receptors . However, characterization of high‐resolution structures of the clusters has not been possible, mostly due to difficulties in making full‐length receptors and reconstituting complete signaling complexes in a membrane environment.…”

Section: Dimerization and Activation Of Tlrsmentioning

confidence: 99%

Sensing of microbial molecular patterns by Toll‐like receptors

Song

Lee

2012

Immunological Reviews

157

153

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Toll-like receptors (TLRs) sense structural patterns in microbial molecules and initiate immune defense mechanisms. The structures of many extracellular and intracellular domains of TLRs have been studied in the last 10 years. These structures reveal the extraordinary diversity of TLR-ligand interactions. Some TLRs use internal hydrophobic pockets to bind bacterial ligands and others use solvent-exposed surfaces to bind hydrophilic ligands. The structures suggest a common activation mechanism for TLRs: ligand binding to extracellular domains induces dimerization of the intracellular domains and so activates intracellular signaling pathways. Recently, the structure of the death domain complex of one of the signaling adapters, myeloid differentiation factor 88 (MyD88), has been determined. This structure shows how aggregation of signaling adapters recruits downstream kinases. However, we are still far from a complete understanding of TLR activation. We need to study the structures of TLR7-10 in complex with their ligands. We also need to determine the structures of TLR-adapter aggregates to understand activation mechanisms and the specificity of the signaling pathways. Ultimately, we will have to study the structures of the complete TLR signaling complexes containing full-length receptors, ligands, signaling, and bridging adapters, and some of the downstream kinases to understand how TLRs sense microbial infections and activate immune responses against them.

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“…It has recently been shown that TLR3 is able to recognized long double-stranded RNA through lateral clustering of TLR3 units along the length of the dsRNA ligand [54]. Fibril recognition by TLR2 could occur in a similar way along the fibril.…”

Section: Discussionmentioning

confidence: 99%

Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure

Gustot

Raussens

Dehousse

et al. 2013

Cell. Mol. Life Sci.

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Lateral Clustering of TLR3:dsRNA Signaling Units Revealed by TLR3ecd:3Fabs Quaternary Structure

Cited by 40 publications

References 40 publications

Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling

Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling

Sensing of microbial molecular patterns by Toll‐like receptors

Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure

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