Structural basis for TIR domain–mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Mohammad K. Manik
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Mengqi Pan
School of Chemistry and Molecular Biosciences, University of Queensland
Le Xiao
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Weixi Gu
School of Chemistry and Molecular Biosciences, University of Queensland
Hyoyoung Kim
School of Chemistry and Molecular Biosciences, University of Queensland
Sabrina Pospich
Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology
Andrew Hedger
School of Chemistry and Molecular Biosciences, University of Queensland
Parimala R. Vajjhala
School of Chemistry and Molecular Biosciences, University of Queensland
Morris Y. L. Lee
School of Chemistry and Molecular Biosciences, University of Queensland
Xiaoqi Qian
School of Chemistry and Molecular Biosciences, University of Queensland
Michael J. Landsberg
School of Chemistry and Molecular Biosciences, University of Queensland
Thomas Ve
Institute for Biomedicine and Glycomics, Griffith University
Jeffrey D. Nanson
School of Chemistry and Molecular Biosciences, University of Queensland
Stefan Raunser
Katryn J. Stacey
School of Chemistry and Molecular Biosciences, University of Queensland
Hao Wu
Bostjan Kobe
The University of Queensland, School of Chemistry and Molecular Biosciences, Australian Infectious Diseases Research Centre and Institute for Molecular Bioscience