Structural basis for TIR domain–mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM

Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR domain-containing adaptor-inducing interferon-β) and TRAM (TRIF-related adaptor molecule) are essential for MyD88-independent TLR signaling. However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear. Here, we present cryo-EM structures of filaments formed by TRIF and TRAM TIR domains at resolutions of 3.3 Å and 5.6 Å, respectively. Both structures reveal two-stranded parallel helical arrangements. Functional studies underscore the importance of intrastrand interactions, mediated by the BB-loop, and interstrand interactions in TLR4-mediated signaling. We also report the crystal structure of the monomeric TRAM TIR domain bearing the BB loop mutation C117H, which reveals conformational differences consistent with its inactivity. Our findings suggest a unified signaling mechanism by the TIR domains of the four signaling TLR adaptors MyD88, MAL, TRIF, and TRAM and reveal potential therapeutic targets for immunity-related disorders.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-01-09
DOI
https://doi.org/10.1073/pnas.2418988122
Citations
16
Primary Topic
Immune Response and Inflammation
Type
article
Field-Weighted Citation Impact
12.76

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article

Structural basis for TIR domain–mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM

Andrew Hedger, Mengqi Pan, Morris Y. L. Lee, Jeffrey D. Nanson et al.
16 citations
Proceedings of the National Academy of Sciences
Immune Response and Inflammation
12.76
article

Structural basis for TIR domain–mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM

Andrew Hedger, Mengqi Pan, Morris Y. L. Lee, Jeffrey D. Nanson, Hao Wu, Xiaoqi Qian, Stefan Raunser, M.K. Manik, Weixi Gu, Le Xiao, Katryn J. Stacey, Boštjan Kobe, Thomas Ve, Michael J. Landsberg, Sabrina Pospich, Parimala R. Vajjhala, Hyoyoung Kim
article en
16 citations

Abstract

Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR domain-containing adaptor-inducing interferon-β) and TRAM (TRIF-related adaptor molecule) are essential for MyD88-independent TLR signaling. However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear. Here, we present cryo-EM structures of filaments formed by TRIF and TRAM TIR domains at resolutions of 3.3 Å and 5.6 Å, respectively. Both structures reveal two-stranded parallel helical arrangements. Functional studies underscore the importance of intrastrand interactions, mediated by the BB-loop, and interstrand interactions in TLR4-mediated signaling. We also report the crystal structure of the monomeric TRAM TIR domain bearing the BB loop mutation C117H, which reveals conformational differences consistent with its inactivity. Our findings suggest a unified signaling mechanism by the TIR domains of the four signaling TLR adaptors MyD88, MAL, TRIF, and TRAM and reveal potential therapeutic targets for immunity-related disorders.

Proceedings of the National Academy of SciencesVol. 122(2)
Griffith University (AU), Boston Children's Hospital (US), Harvard University (US), Charles Sturt University (AU), The University of Queensland (AU), Institute for Biomedicine (IT), Max Planck Institute of Molecular Physiology (DE)
Cancer Research Institute, Australian Synchrotron, Max-Planck-Gesellschaft, National Institutes of Health, Medical Research Council, National Health and Medical Research Council
Openalex Percentile: Top 1%
Immune Response and Inflammation
12.76
DOIOpen Access PDFOpenAlex
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