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Crystal Structure of the N terminal domain of TRIF (TIR-domain- containing adapter-inducing interferon-beta)
Structural highlights
DiseaseTCAM1_HUMAN Herpetic encephalitis. Herpes simplex encephalitis 4 (HSE4) [MIM:614850: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.[1] FunctionTCAM1_HUMAN Involved in innate immunity against invading pathogens. Adapter used by TLR3 and TLR4 (through TICAM2) to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively.[2] [3] [4] Publication Abstract from PubMedTRIF/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 A 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-NTD(A66M/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-kappaB-dependent reporter-gene activity. These findings thus identify opportunities for the selective targeting of TLR3- and TLR4-mediated inflammation. The TLR signalling adaptor TRIF/TICAM-1 has an N-terminal helical domain with structural similarity to IFIT proteins.,Ullah MO, Ve T, Mangan M, Alaidarous M, Sweet MJ, Mansell A, Kobe B Acta Crystallogr D Biol Crystallogr. 2013 Dec;69(Pt 12):2420-30. doi:, 10.1107/S0907444913022385. Epub 2013 Nov 19. PMID:24311583[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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