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

Guven-Maiorov E, Keskin O, Gursoy A, VanWaes C, Chen Z, Tsai CJ, Nussinov R - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.

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.

No MeSH data available.


Related in: MedlinePlus

Parallel downstream pathways of TLRs, which lead to distinct outcomes, are mutually exclusive.Green arrows shows that TRIF- and MyD88-dependent paths cannot be activated simultaneously due to shared binding sites on TLR4-dimer or steric hindrance. Blue arrows demonstrate that TRAF6 and TRAF3 bind to overlapping interfaces on MyD88 DD (downstream of endosomal TLRs). Pink arrows shows that IRAK4 and FADD will have steric clash when they bind to MyD88 at the same time. The three branches of TLR pathway, namely pro-inflammatory, interferon and anti-inflammatory, and apoptotic paths are mutually exclusive.
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f8: Parallel downstream pathways of TLRs, which lead to distinct outcomes, are mutually exclusive.Green arrows shows that TRIF- and MyD88-dependent paths cannot be activated simultaneously due to shared binding sites on TLR4-dimer or steric hindrance. Blue arrows demonstrate that TRAF6 and TRAF3 bind to overlapping interfaces on MyD88 DD (downstream of endosomal TLRs). Pink arrows shows that IRAK4 and FADD will have steric clash when they bind to MyD88 at the same time. The three branches of TLR pathway, namely pro-inflammatory, interferon and anti-inflammatory, and apoptotic paths are mutually exclusive.

Mentions: Taken together, the TLR4 architectures indicate that all TLR’s parallel downstream pathways are competitive (Fig. 8). MyD88- and TRIF-dependent pathways downstream of a single TLR4-dimer cannot be activated simultaneously due to shared binding site. If MyD88 is recruited to the activated TLRs, it uses its TIR domain to interact with the bridging adaptor protein Mal/TIRAP and its DD to interact with the other downstream partners, IRAKs, TRAF6, TRAF3, and FADD. These trigger three alternative parallel pathways and lead to distinct/opposing outcomes.


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

Guven-Maiorov E, Keskin O, Gursoy A, VanWaes C, Chen Z, Tsai CJ, Nussinov R - Sci Rep (2015)

Parallel downstream pathways of TLRs, which lead to distinct outcomes, are mutually exclusive.Green arrows shows that TRIF- and MyD88-dependent paths cannot be activated simultaneously due to shared binding sites on TLR4-dimer or steric hindrance. Blue arrows demonstrate that TRAF6 and TRAF3 bind to overlapping interfaces on MyD88 DD (downstream of endosomal TLRs). Pink arrows shows that IRAK4 and FADD will have steric clash when they bind to MyD88 at the same time. The three branches of TLR pathway, namely pro-inflammatory, interferon and anti-inflammatory, and apoptotic paths are mutually exclusive.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544004&req=5

f8: Parallel downstream pathways of TLRs, which lead to distinct outcomes, are mutually exclusive.Green arrows shows that TRIF- and MyD88-dependent paths cannot be activated simultaneously due to shared binding sites on TLR4-dimer or steric hindrance. Blue arrows demonstrate that TRAF6 and TRAF3 bind to overlapping interfaces on MyD88 DD (downstream of endosomal TLRs). Pink arrows shows that IRAK4 and FADD will have steric clash when they bind to MyD88 at the same time. The three branches of TLR pathway, namely pro-inflammatory, interferon and anti-inflammatory, and apoptotic paths are mutually exclusive.
Mentions: Taken together, the TLR4 architectures indicate that all TLR’s parallel downstream pathways are competitive (Fig. 8). MyD88- and TRIF-dependent pathways downstream of a single TLR4-dimer cannot be activated simultaneously due to shared binding site. If MyD88 is recruited to the activated TLRs, it uses its TIR domain to interact with the bridging adaptor protein Mal/TIRAP and its DD to interact with the other downstream partners, IRAKs, TRAF6, TRAF3, and FADD. These trigger three alternative parallel pathways and lead to distinct/opposing outcomes.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.

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.

No MeSH data available.


Related in: MedlinePlus