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Structural insights into TIR domain specificity of the bridging adaptor Mal in TLR4 signaling.

ABSTRACT: MyD88 adaptor-like protein (Mal) is a crucial adaptor that acts as a bridge to recruit the MyD88 molecule to activated TLR4 receptors in response to invading pathogens. The specific assembly of the Toll/interleukin-1 receptor (TIR) domains of TLR4, Mal and MyD88 is responsible for proper signal transduction in the TLR4 signaling pathway. However, the molecular mechanism for the specificity of these TIR domains remains unclear. Here, we present the crystal structure of the TIR domain of the human Mal molecule (Mal-TIR) at a resolution of 2.4 Å. Unexpectedly, Mal-TIR exhibits an extraordinarily long AB loop, but no ?B helix or BB loop, distinguishing it from other TIR domains. More importantly, the Mal-TIR AB loop is capable of mediating direct binding to the TIR domains of TLR4 and MyD88 simultaneously. We also found that Mal-TIR can form a back-to-back dimer that may resemble the dimeric assembly of the entire Mal molecule. Our data demonstrate the bridge role of the Mal-TIR domain and provide important information about TIR domain specificity.

SUBMITTER: Lin Z

PROVIDER: S-EPMC3317499 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Structural insights into TIR domain specificity of the bridging adaptor Mal in TLR4 signaling.

Lin Zhijie Z Lu Jing J Zhou Weihong W Shen Yuequan Y

PloS one 20120402 4

MyD88 adaptor-like protein (Mal) is a crucial adaptor that acts as a bridge to recruit the MyD88 molecule to activated TLR4 receptors in response to invading pathogens. The specific assembly of the Toll/interleukin-1 receptor (TIR) domains of TLR4, Mal and MyD88 is responsible for proper signal transduction in the TLR4 signaling pathway. However, the molecular mechanism for the specificity of these TIR domains remains unclear. Here, we present the crystal structure of the TIR domain of the human ...[more]

PMID: 22485159

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Project description:BackgroundTRIF is a key protein in antiviral innate immunity, operating downstream of TLRs. TRIF activation leads to the production of interferon-β and pro-inflammatory cytokines. There is evidence from experiments to suggest that the N-terminal domain of TRIF binds to its TIR domain to avoid constitutive activation. However, no structure of a complex between the N-terminal domain and the TIR domain exists till date. The disordered nature of the region connecting the N-terminal domain and the TIR domain compounds the issue of elucidating the mechanism of autoinhibition of TRIF. In this study, we have employed an integrative approach consisting of mutual information analysis, docking, molecular dynamics simulations and residue network analysis, in combination with existing experimental data to provide a glimpse of TRIF in its autoinhibited state.ResultsOur extensive docking approach reveals that the N-terminal domain binds to the BB loop-B helix region of the TIR domain, consistent with experimental observations. Long length molecular dynamics simulations of 1 microsecond performed on the docked model highlights residues participating in hydrogen bonding and hydrophobic interactions at the interface. A pair of residues present in the vicinity of the interface is also predicted by mutual information analysis, to co-evolve. Residues mediating long-range interactions within the TIR domain of TRIF were identified using residue network analysis.ConclusionsBased on the results of the modelling and residue network analysis, we propose that the N-terminal domain binds to the BB loop region of the TIR domain, thereby preventing its homodimersation. The binding of TRIF to TLR3 or TRAM could induce a slight conformational change, causing the interactions between the N-terminal domain and TIR domain to disrupt, thereby exposing the BB loop and rendering it amenable for higher-order oligomerisation.ReviewersThis article was reviewed by Michael Gromiha, Srikrishna Subramaniam and Peter Bond (nominated by Chandra Verma).

Dataset Information

Structural insights into TIR domain specificity of the bridging adaptor Mal in TLR4 signaling.

Publications

Structural insights into TIR domain specificity of the bridging adaptor Mal in TLR4 signaling.

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