ArticleProceedings of the National Academy of Sciences of the United States of America2025
Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 15 papers, 2 of them syntheses that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
15 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Uncovering Necroptosis in Alzheimer's Disease: A Systematic Review of Evidence Across Experimental Models.Cellular and molecular neurobiology · 2025Pooled it
- TIR domain proteins: regulatory mechanisms in the tumor immune microenvironment, clinical translation strategies, and prospects for precision therapy applications.Frontiers in immunology · 2025Pooled it
- The cell-type-specific roles of Toll-like receptors in herpes simplex virus infection and pathogenesis.Virulence · 2026Review
- One adaptor, multiple outcomes: decoding TRIFosome heterogeneity.Biochemical Society transactions · 2026Review
- Review
- Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome.Science advances · 2026Article
- Conformation-programmed DNA computing.Science advances · 2026Article
- Immune signaling as a determinant of cellular identity and tissue function.Frontiers in immunology · 2026Review
- Gut microbiota in Henoch-Schönlein purpura: from pathogenesis to therapeutic strategies.Frontiers in immunology · 2026Review
- Molecular characterisation of the Bacillus subtilis SpbK antiphage defence system.Nature communications · 2025Article
- Structural basis for ACT1 oligomerization induced by IL-17 receptor hetero-tetramer.Nature communications · 2025Article
- Filament formation and NAD processing by noncanonical human FAM118 sirtuins.Nature structural & molecular biology · 2025Article
- Signalling by co-operative higher-order assembly formation: linking evidence at molecular and cellular levels.The Biochemical journal · 2025Review
- Toll-like receptor-mediated immune imbalance in asthma: controversies, breakthroughs, and future directions.Frontiers in immunology · 2025Review
- Pattern recognition receptors and their roles in antiviral innate immunity in livestock.Frontiers in immunology · 2025Review
Corrections and comments
- Erratum issued
Authors and funding
17 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.