Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling

Biochem Soc Trans. 2017 Aug 15;45(4):929-935. doi: 10.1042/BST20160259. Epub 2017 Jun 19.


Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS), produces pro-inflammatory cytokines and type I interferons, and associates with a trigger of endotoxin shock. TLR4 is interacted with a TIR domain-containing adaptor molecule-2 (TICAM-2)/TRAM [TRIF (TIR domain-containing adaptor-inducing interferon-β)-related adaptor molecule] via its Toll-interleukin-1 receptor homology (TIR) domain. TICAM-2 acts as a scaffold protein and activates TIR domain-containing adaptor molecule-1 (TICAM-1)/TRIF. According to the structural analysis by NMR, TICAM-2 interacts with TICAM-1 by the acidic amino acids motif, E87/D88/D89. The TIR domain of TICAM-2 couples with the dimer of TIR domain of TLR4 beneath the membrane, and TICAM-2 itself also forms dimer and constitutes a binding site with TICAM-1. Endosomal localization of TICAM-2 is essential for TLR4-mediated type I interferon-inducing signal from the endosome. N-terminal myristoylation allows TICAM-2 to anchor to the endosomal membrane. Additionally, we have identified two acidic amino acids, D91/E92, as a functional motif that cooperatively determines endosomal localization of TICAM-2. This structural information of TICAM-2 suggests that the specific structure is indispensable for the endosomal localization and type I interferon production of TICAM-2. Taken together with the knowledge on cytoplasmic sensors for LPS, TICAM-2/TICAM-1 may conform to a signal network on TLR4 to facilitate induction of cytokine disorders.

Keywords: TICAM-2 adaptor; TLR4; endotoxin; innate immunity; myeloid cells.

Publication types

  • Review

MeSH terms

  • Acylation
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adaptor Proteins, Vesicular Transport / chemistry
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Amino Acid Motifs
  • Animals
  • Dimerization
  • Endosomes / metabolism*
  • Humans
  • Interferon Type I / metabolism
  • Models, Biological*
  • Myristic Acid / metabolism
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Protein Processing, Post-Translational*
  • Protein Transport
  • Signal Transduction*
  • Toll-Like Receptor 4 / agonists*
  • Toll-Like Receptor 4 / chemistry
  • Toll-Like Receptor 4 / metabolism


  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Interferon Type I
  • TICAM1 protein, human
  • TICAM2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Myristic Acid