The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway

Emine Guven-Maiorov, Ozlem Keskin, Attila Gursoy*, Carter VanWaes, Zhong Chen, Chung Jung Tsai, Ruth Nussinov

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro- and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster. The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro- and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro- and anti-inflammatory pathways. The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD. Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points. The architectures are compatible with the currently-available experimental data and provide compelling insights into signaling in cancer and inflammation pathways.

Original languageEnglish
Article number13128
JournalScientific Reports
Volume5
DOIs
StatePublished - 21 Aug 2015

Funding

FundersFunder number
TUBITAK projects113E164, 114M196
National Institutes of HealthHHSN261200800001E
National Cancer InstituteZIABC010441
Frederick National Laboratory for Cancer Research

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