Interactive Sites in the MyD88 Toll/Interleukin (IL) 1 Receptor Domain Responsible for Coupling to the IL1β Signaling Pathway

Li, Chunsheng; Zienkiewicz, Józef; Hawiger, Jacek

doi:10.1074/jbc.m503262200

Cited by 106 publications

(89 citation statements)

References 27 publications

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“…When a TIR mutant harboring a substitution of a functionally important residue is expressed, such suppression is alleviated, which leads to higher LPS-induced luciferase activity than observed with a TIR domain harboring the wild-type sequence. It should be noted that the dominant negative effect of ectopically expressed TIR domain has been used for functional analysis of some key residues of MyD88-TIR in IL-1 signaling (11).…”

Section: Cell-based Functional Assays Of the Myd88 Tir Domain In Tlr4mentioning

confidence: 99%

“…However, the functional relevance of these homomeric interactions remains obscure because the formation of a homomeric dimer in these TIR domains has not been observed in solution (9,10). Based on crystal structures and mutational data, several structural models have been proposed for heteromeric TIR-TIR interactions, which commonly suggest the importance of the so-called BB loop in these interactions (11,12).…”

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confidence: 99%

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Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling

Ohnishi

Tochio

Kato

et al. 2009

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

191

185

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Section: Cell-based Functional Assays Of the Myd88 Tir Domain In Tlr4mentioning

confidence: 99%

mentioning

confidence: 99%

Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling

Ohnishi

Tochio

Kato

et al. 2009

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

191

185

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“…Despite extensive structural studies, it is not known why homotypic interactions are essential for downstream signaling (20)(21)(22)(23)(24)(25)(26)(27). To address this issue, it is necessary to discriminate residues required for homotypic and those required for heterotypic interactions.…”

mentioning

confidence: 99%

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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“…For this reason, they have been the subject of numerous structural and functional studies aimed at identifying the residues participating to homo and hetero interactions (21)(22)(23)(24)(25)(26). In the case of MyD88, it was demonstrated that the BB loop of the TIR domain plays a role in homodimerization (22,27,28).…”

mentioning

confidence: 99%

Mutational Analysis Identifies Residues Crucial for Homodimerization of Myeloid Differentiation Factor 88 (MyD88) and for Its Function in Immune Cells

Loiarro

Volpe

Ruggiero

et al. 2013

Journal of Biological Chemistry

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Background:MyD88 is an adaptor protein that plays a crucial role in the immune response. Results: We identified residues within the TIR domain of MyD88 required for protein self-association. Conclusion: Interference with the surface of homodimerization identified by these residues inhibits MyD88 function. Significance: The inhibition of MyD88 activity could be a good therapeutic strategy for inflammatory and autoimmune diseases.

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Interactive Sites in the MyD88 Toll/Interleukin (IL) 1 Receptor Domain Responsible for Coupling to the IL1β Signaling Pathway

Abstract: Myeloid differentiation factor

Cited by 106 publications

References 27 publications

Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling

Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling

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

Mutational Analysis Identifies Residues Crucial for Homodimerization of Myeloid Differentiation Factor 88 (MyD88) and for Its Function in Immune Cells

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