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

Ullah, M. Obayed, Ve, Thomas, Mangan, Matthew, Alaidarous, Mohammed, Sweet, Matthew J., Mansell, Ashley and Kobe, Bostjan (2013) The TLR signalling adaptor TRIF/TICAM-1 has an N-terminal helical domain with structural similarity to IFIT proteins. Acta Crystallographica Section D: Biological Crystallography, 69 12: 2420-2430. doi:10.1107/S0907444913022385

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Author Ullah, M. Obayed
Ve, Thomas
Mangan, Matthew
Alaidarous, Mohammed
Sweet, Matthew J.
Mansell, Ashley
Kobe, Bostjan
Title The TLR signalling adaptor TRIF/TICAM-1 has an N-terminal helical domain with structural similarity to IFIT proteins
Journal name Acta Crystallographica Section D: Biological Crystallography   Check publisher's open access policy
ISSN 0907-4449
Publication date 2013-12
Sub-type Article (original research)
DOI 10.1107/S0907444913022385
Open Access Status File (Publisher version)
Volume 69
Issue 12
Start page 2420
End page 2430
Total pages 11
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell Publishing
Collection year 2014
Language eng
Formatted abstract
TRIF/TICAM-1 (TIR domain-containing adaptor inducing interferon-β/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-β promoter, as well as NF-κB-dependent reporter-gene activity. These findings thus identify opportunities for the selective targeting of TLR3- and TLR4-mediated inflammation.
Keyword Toll-like receptor adaptor protein
Innate immunity
Tetratricopeptide repeat
IFIT proteins
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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Created: Wed, 16 Oct 2013, 11:21:02 EST by Anna Cotroneo on behalf of School of Chemistry & Molecular Biosciences