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TitleStructural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 2, Page e2418988122, Year 2025
Publish dateJan 14, 2025
AuthorsMohammad K Manik / Mengqi Pan / Le Xiao / Weixi Gu / Hyoyoung Kim / Sabrina Pospich / Andrew Hedger / Parimala R Vajjhala / Morris Y L Lee / Xiaoqi Qian / Michael J Landsberg / Thomas Ve / Jeffrey D Nanson / Stefan Raunser / Katryn J Stacey / Hao Wu / Bostjan Kobe /
PubMed AbstractInnate 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 ...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.
External linksProc Natl Acad Sci U S A / PubMed:39786929
MethodsEM (helical sym.) / X-ray diffraction
Resolution3 - 5.6 Å
Structure data

46946

9dk8

EMDB-46946, PDB-9dk8:
TRIF TIR Filament Cryo-EM Structure
Method: EM (helical sym.) / Resolution: 3.3 Å

46977

9dlg

EMDB-46977, PDB-9dlg:
CryoEM structure of the TIR domain from human TRAM
Method: EM (helical sym.) / Resolution: 5.6 Å

PDB-9dki:
Crystal structure of the TIR domain C117H mutant from human TRAM
Method: X-RAY DIFFRACTION / Resolution: 3 Å

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / TRIF / TICAM 1 / TIR domain / innate immune system / Toll-like receptor / TRAM / TIR

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