| Structural highlights
Function
TCAM2_HUMAN Functions as sorting adapter in LPS-TLR4 signaling to regulate the MYD88-independent pathway during the innate immune response to LPS. Physically bridges TLR4 and TICAM1 and functionally transmits LPS-TRL4 signal to TICAM1; signaling is proposed to occur in early endosomes after endocytosis of TLR4. May also be involved in IL1-triggered NF-kappa-B activation, functioning upstream of IRAK1, IRAK2, TRAF6, and IKBKB; however, reports are controversial. Involved in IL-18 signaling and is proposed to function as a sorting adaptor for MYD88 in IL-18 signaling during adaptive immune response.[1] [2] [3] [4] [5] [6] [7] Isoform 2: Proposed to inhibit LPS-TLR4 signaling at the late endosome by interaction with isoform 1 thereby disrupting the association of isoform 1 with TICAM1. May be involved in TLR4 degradation in late endosomes.[8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR domain-containing adaptor-inducing interferon-beta) and TRAM (TRIF-related adaptor molecule) are essential for MyD88-independent TLR signaling. However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear. Here, we present cryo-EM structures of filaments formed by TRIF and TRAM TIR domains at resolutions of 3.3 A and 5.6 A, respectively. Both structures reveal two-stranded parallel helical arrangements. Functional studies underscore the importance of intrastrand interactions, mediated by the BB-loop, and interstrand interactions in TLR4-mediated signaling. We also report the crystal structure of the monomeric TRAM TIR domain bearing the BB loop mutation C117H, which reveals conformational differences consistent with its inactivity. Our findings suggest a unified signaling mechanism by the TIR domains of the four signaling TLR adaptors MyD88, MAL, TRIF, and TRAM and reveal potential therapeutic targets for immunity-related disorders.
Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM.,Manik MK, Pan M, Xiao L, Gu W, Kim H, Pospich S, Hedger A, Vajjhala PR, Lee MYL, Qian X, Landsberg MJ, Ve T, Nanson JD, Raunser S, Stacey KJ, Wu H, Kobe B Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2418988122. doi: , 10.1073/pnas.2418988122. Epub 2025 Jan 9. PMID:39786929[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bin LH, Xu LG, Shu HB. TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling. J Biol Chem. 2003 Jul 4;278(27):24526-32. Epub 2003 Apr 28. PMID:12721283 doi:https://dx.doi.org/10.1074/jbc.M303451200
- ↑ Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T. TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem. 2003 Dec 12;278(50):49751-62. Epub 2003 Sep 30. PMID:14519765 doi:https://dx.doi.org/10.1074/jbc.M305820200
- ↑ Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, Monks B, Pitha PM, Golenbock DT. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med. 2003 Oct 6;198(7):1043-55. Epub 2003 Sep 29. PMID:14517278 doi:https://dx.doi.org/10.1084/jem.20031023
- ↑ PMID: https://pubmed.ncbi.nlm.nih.gov/194121844/
- ↑ Rowe DC, McGettrick AF, Latz E, Monks BG, Gay NJ, Yamamoto M, Akira S, O'Neill LA, Fitzgerald KA, Golenbock DT. The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6299-304. Epub 2006 Apr 7. PMID:16603631 doi:https://dx.doi.org/10.1073/pnas.0510041103
- ↑ McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ, Fitzgerald KA, O'Neill LA. Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9196-201. Epub 2006 Jun 6. PMID:16757566 doi:https://dx.doi.org/10.1073/pnas.0600462103
- ↑ Ohnishi H, Tochio H, Kato Z, Kawamoto N, Kimura T, Kubota K, Yamamoto T, Funasaka T, Nakano H, Wong RW, Shirakawa M, Kondo N. TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88. PLoS One. 2012;7(6):e38423. doi: 10.1371/journal.pone.0038423. Epub 2012 Jun 7. PMID:22685567 doi:https://dx.doi.org/10.1371/journal.pone.0038423
- ↑ Bin LH, Xu LG, Shu HB. TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling. J Biol Chem. 2003 Jul 4;278(27):24526-32. Epub 2003 Apr 28. PMID:12721283 doi:https://dx.doi.org/10.1074/jbc.M303451200
- ↑ Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T. TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem. 2003 Dec 12;278(50):49751-62. Epub 2003 Sep 30. PMID:14519765 doi:https://dx.doi.org/10.1074/jbc.M305820200
- ↑ Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, Monks B, Pitha PM, Golenbock DT. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med. 2003 Oct 6;198(7):1043-55. Epub 2003 Sep 29. PMID:14517278 doi:https://dx.doi.org/10.1084/jem.20031023
- ↑ PMID: https://pubmed.ncbi.nlm.nih.gov/194121844/
- ↑ Rowe DC, McGettrick AF, Latz E, Monks BG, Gay NJ, Yamamoto M, Akira S, O'Neill LA, Fitzgerald KA, Golenbock DT. The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6299-304. Epub 2006 Apr 7. PMID:16603631 doi:https://dx.doi.org/10.1073/pnas.0510041103
- ↑ McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ, Fitzgerald KA, O'Neill LA. Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9196-201. Epub 2006 Jun 6. PMID:16757566 doi:https://dx.doi.org/10.1073/pnas.0600462103
- ↑ Ohnishi H, Tochio H, Kato Z, Kawamoto N, Kimura T, Kubota K, Yamamoto T, Funasaka T, Nakano H, Wong RW, Shirakawa M, Kondo N. TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88. PLoS One. 2012;7(6):e38423. doi: 10.1371/journal.pone.0038423. Epub 2012 Jun 7. PMID:22685567 doi:https://dx.doi.org/10.1371/journal.pone.0038423
- ↑ Manik MK, Pan M, Xiao L, Gu W, Kim H, Pospich S, Hedger A, Vajjhala PR, Lee MYL, Qian X, Landsberg MJ, Ve T, Nanson JD, Raunser S, Stacey KJ, Wu H, Kobe B. Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM. Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2418988122. PMID:39786929 doi:10.1073/pnas.2418988122
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