Acta Crystallographica Section D

Biological Crystallography

Volume 69, Part 12 (December 2013)

research papers

Acta Cryst. (2013). D69, 2420-2430    [ doi:10.1107/S0907444913022385 ]

The TLR signalling adaptor TRIF/TICAM-1 has an N-­terminal helical domain with structural similarity to IFIT proteins

M. O. Ullah, T. Ve, M. Mangan, M. Alaidarous, M. J. Sweet, A. Mansell and B. Kobe

Abstract: TRIF/TICAM-1 (TIR domain-containing adaptor inducing interferon-[beta]/TIR domain-containing adaptor molecule 1) is the adaptor protein in the Toll-like receptor (TLR) 3 and 4 signalling pathway that leads to the production of type 1 interferons and cytokines. The signalling involves TIR (Toll/interleukin-1 receptor) domain-dependent TRIF oligomerization. A protease-resistant N-terminal region is believed to be involved in self-regulation of TRIF by interacting with its TIR domain. Here, the structural and functional characterization of the N-terminal domain of TRIF (TRIF-NTD) comprising residues 1-153 is reported. The 2.22 Å resolution crystal structure was solved by single-wavelength anomalous diffraction (SAD) using selenomethionine-labelled crystals of TRIF-NTD containing two additional introduced Met residues (TRIF-NTDA66M/L113M). The structure consists of eight antiparallel helices that can be divided into two subdomains, and the overall fold shares similarity to the interferon-induced protein with tetratricopeptide repeats (IFIT) family of proteins, which are involved in both the recognition of viral RNA and modulation of innate immune signalling. Analysis of TRIF-NTD surface features and the mapping of sequence conservation onto the structure suggest several possible binding sites involved in either TRIF auto-regulation or interaction with other signalling molecules or ligands. TRIF-NTD suppresses TRIF-mediated activation of the interferon-[beta] promoter, as well as NF-[kappa]B-dependent reporter-gene activity. These findings thus identify opportunities for the selective targeting of TLR3- and TLR4-mediated inflammation.

PDB references: 4bsx and 4c0m

Keywords: Toll-like receptor adaptor protein; innate immunity; TRIF; TICAM-1; tetratricopeptide repeat; IFIT proteins.

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Supplementary Figures S1-S9


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