9DKI

Crystal structure of the TIR domain C117H mutant from human TRAM

Summary for 9DKI

• Entry DOI: 10.2210/pdb9dki/pdb
• Descriptor: TIR domain-containing adapter molecule 2 (1 entity in total)
• Functional Keywords: toll-like receptor, tir domain, tram, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 16354.44

Authors

Pan, M.,Gu, W.,Nanson, J.D.,Kobe, B. (deposition date: 2024-09-09, release date: 2025-01-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3 Å)