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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

MyD88- and TRIF- dependent downstream TLR pathways are mutually exclusive.(a) TRAM-homodimer has a steric clash with Mal-homodimer when superimposed to BB TLR4-homodimer model, and thus they are mutually exclusive: either Mal or TRAM homodimers can bind to TLR4 at any time. TRAM and Mal interactions are mutually exclusive in BB TLR4-homodimers and this is in line with the findings of several studies182122. This indicates that MyD88-dependent pro-inflammatory and TRIF-dependent anti-inflammatory pathways are competitive. (b) TRAM-homodimer does not overlap with Mal-homodimer when superimposed to FF TLR4-homodimer model. (c) MyD88 overlaps with TRIF on TLR4: the FF TLR4-homodimer model has steric clashes of MyD88 and TRIF when superimposed Mal-MyD88 and TRAM-TRIF. Red box indicates the location of steric clash.
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f6: MyD88- and TRIF- dependent downstream TLR pathways are mutually exclusive.(a) TRAM-homodimer has a steric clash with Mal-homodimer when superimposed to BB TLR4-homodimer model, and thus they are mutually exclusive: either Mal or TRAM homodimers can bind to TLR4 at any time. TRAM and Mal interactions are mutually exclusive in BB TLR4-homodimers and this is in line with the findings of several studies182122. This indicates that MyD88-dependent pro-inflammatory and TRIF-dependent anti-inflammatory pathways are competitive. (b) TRAM-homodimer does not overlap with Mal-homodimer when superimposed to FF TLR4-homodimer model. (c) MyD88 overlaps with TRIF on TLR4: the FF TLR4-homodimer model has steric clashes of MyD88 and TRIF when superimposed Mal-MyD88 and TRAM-TRIF. Red box indicates the location of steric clash.

Mentions: TRAM homodimer formation is required for TRIF recruitment. Supplementary Fig. S5 displays the TLR4-homodimers that are bound to TRAM-homodimers. Supplementary Fig. S6 shows TLR4-TRAM-TRIF interactions with two TLR4-homodimers. When we superimpose the Mal-homodimers onto these TLR4-TRAM, we observe that TRAM and Mal interactions are mutually exclusive in the BB TLR4-homodimer since they have overlapping binding sites on TLR4 (Fig. 6a), but not with the FF TLR4 dimer (Fig. 6b). Proteins that bind to identical or overlapping interfaces on a protein will have a steric clash and thus cannot bind simultaneously45.


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)

MyD88- and TRIF- dependent downstream TLR pathways are mutually exclusive.(a) TRAM-homodimer has a steric clash with Mal-homodimer when superimposed to BB TLR4-homodimer model, and thus they are mutually exclusive: either Mal or TRAM homodimers can bind to TLR4 at any time. TRAM and Mal interactions are mutually exclusive in BB TLR4-homodimers and this is in line with the findings of several studies182122. This indicates that MyD88-dependent pro-inflammatory and TRIF-dependent anti-inflammatory pathways are competitive. (b) TRAM-homodimer does not overlap with Mal-homodimer when superimposed to FF TLR4-homodimer model. (c) MyD88 overlaps with TRIF on TLR4: the FF TLR4-homodimer model has steric clashes of MyD88 and TRIF when superimposed Mal-MyD88 and TRAM-TRIF. Red box indicates the location of steric clash.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: MyD88- and TRIF- dependent downstream TLR pathways are mutually exclusive.(a) TRAM-homodimer has a steric clash with Mal-homodimer when superimposed to BB TLR4-homodimer model, and thus they are mutually exclusive: either Mal or TRAM homodimers can bind to TLR4 at any time. TRAM and Mal interactions are mutually exclusive in BB TLR4-homodimers and this is in line with the findings of several studies182122. This indicates that MyD88-dependent pro-inflammatory and TRIF-dependent anti-inflammatory pathways are competitive. (b) TRAM-homodimer does not overlap with Mal-homodimer when superimposed to FF TLR4-homodimer model. (c) MyD88 overlaps with TRIF on TLR4: the FF TLR4-homodimer model has steric clashes of MyD88 and TRIF when superimposed Mal-MyD88 and TRAM-TRIF. Red box indicates the location of steric clash.
Mentions: TRAM homodimer formation is required for TRIF recruitment. Supplementary Fig. S5 displays the TLR4-homodimers that are bound to TRAM-homodimers. Supplementary Fig. S6 shows TLR4-TRAM-TRIF interactions with two TLR4-homodimers. When we superimpose the Mal-homodimers onto these TLR4-TRAM, we observe that TRAM and Mal interactions are mutually exclusive in the BB TLR4-homodimer since they have overlapping binding sites on TLR4 (Fig. 6a), but not with the FF TLR4 dimer (Fig. 6b). Proteins that bind to identical or overlapping interfaces on a protein will have a steric clash and thus cannot bind simultaneously45.

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