9dk8 | pdb_00009dk8
TRIF TIR Filament Cryo-EM Structure
Structural highlights
DiseaseTCAM1_HUMAN Herpetic encephalitis. Herpes simplex encephalitis 4 (HSE4) [MIM:614850: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.[1] FunctionTCAM1_HUMAN Involved in innate immunity against invading pathogens. Adapter used by TLR3 and TLR4 (through TICAM2) to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively.[2] [3] [4] Publication Abstract from PubMedInnate 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-beta) 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 A and 5.6 A, 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. Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM.,Manik MK, Pan M, Xiao L, Gu W, Kim H, Pospich S, Hedger A, Vajjhala PR, Lee MYL, Qian X, Landsberg MJ, Ve T, Nanson JD, Raunser S, Stacey KJ, Wu H, Kobe B Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2418988122. doi: , 10.1073/pnas.2418988122. Epub 2025 Jan 9. PMID:39786929[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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