title: Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling.
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.
authors.affiliation: Department of Structural Biology, Faculty of Advanced Life Science, Hokkaido University, N-21, W-11, Kita-ku, Sapporo 001-0021, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Enokizono
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kumeta
authors.forename: Kenji
authors.initials: K
authors.lastname: Funami
authors.forename: Masataka
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Joy
authors.initials: J
authors.lastname: Sarmiento
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamashita
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Inagaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000276:immunology*; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000276:immunology*; D019281:Dimerization; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008156:Luciferases; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008958:Models, Molecular; D016296:Mutagenesis; D011487:Protein Conformation; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C470409:TICAM1 protein, human; C480228:TICAM2 protein, human; D051193:Toll-Like Receptors; D008156:Luciferases
keywords: MyD88-independent pathway; TLR signaling; TRAM; TRIF; innate immunity