Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling

Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19908-13. doi: 10.1073/pnas.1222811110. Epub 2013 Nov 19.

Abstract

Homotypic and heterotypic interactions between Toll/interleukin-1 receptor (TIR) domains in Toll-like receptors (TLRs) and downstream adaptors are essential to evoke innate immune responses. However, such oligomerization properties present intrinsic difficulties in structural studies of TIR domains. Here, using BB-loop mutations that disrupt homotypic interactions, we determined the structures of the monomeric TIR domain-containing adaptor molecule (TICAM)-1 and TICAM-2 TIR domains. Docking of the monomeric structures, together with yeast two hybrid-based mutagenesis assays, reveals that the homotypic interaction between TICAM-2 TIR is indispensable to present a scaffold for recruiting the monomeric moiety of the TICAM-1 TIR dimer. This result proposes a unique idea that oligomerization of upstream TIR domains is crucial for binding of downstream TIR domains. Furthermore, the bivalent nature of each TIR domain dimer can generate a large signaling complex under the activated TLRs, which would recruit downstream signaling molecules efficiently. This model is consistent with previous reports that BB-loop mutants completely abrogate downstream signaling.

Keywords: MyD88-independent pathway; TLR signaling; TRAM; TRIF; innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / immunology*
  • Adaptor Proteins, Vesicular Transport / chemistry
  • Adaptor Proteins, Vesicular Transport / immunology*
  • Dimerization
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Luciferases
  • Magnetic Resonance Spectroscopy
  • Models, Biological*
  • Models, Molecular*
  • Mutagenesis
  • Protein Conformation*
  • Signal Transduction / immunology*
  • Toll-Like Receptors / metabolism*
  • Two-Hybrid System Techniques

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • TICAM1 protein, human
  • TICAM2 protein, human
  • Toll-Like Receptors
  • Luciferases

Associated data

  • PDB/2MLW
  • PDB/2MLX