9DK8

TRIF TIR Filament Cryo-EM Structure

9DK8 の概要

• エントリーDOI: 10.2210/pdb9dk8/pdb
• EMDBエントリー: 46946
• 分子名称: TIR domain-containing adapter molecule 1 (1 entity in total)
• 機能のキーワード: trif, ticam 1, tir domain, innate immune system, immune system
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 351190.06

構造登録者

Manik, M.K.,Xiao, L.,Wu, H. (登録日: 2024-09-08, 公開日: 2025-01-22)

主引用文献

Manik, M.K.,Pan, M.,Xiao, L.,Gu, W.,Kim, H.,Pospich, S.,Hedger, A.,Vajjhala, P.R.,Lee, M.Y.L.,Qian, X.,Landsberg, M.J.,Ve, T.,Nanson, J.D.,Raunser, S.,Stacey, K.J.,Wu, H.,Kobe, B.
Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM.
Proc.Natl.Acad.Sci.USA, 122:e2418988122-e2418988122, 2025

PubMed 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.

PubMed: 39786929
DOI: 10.1073/pnas.2418988122

実験手法

ELECTRON MICROSCOPY (3.3 Å)