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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

Interaction models of Mal-monomer (a,c) and Mal-dimer (b,d) with BB and FF TLR4-homodimer models. Yellow protein is Mal and green spheres show the proposed interface residues of Mal (R184, A185, Y187)27, none of which are at the correct site in the monomeric-Mal-TLR interaction model. However, if dimerization of Mal is also taken into account, it is seen that both monomers are in contact with TLR4, one of which has the interface residue at the correct site.
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f4: Interaction models of Mal-monomer (a,c) and Mal-dimer (b,d) with BB and FF TLR4-homodimer models. Yellow protein is Mal and green spheres show the proposed interface residues of Mal (R184, A185, Y187)27, none of which are at the correct site in the monomeric-Mal-TLR interaction model. However, if dimerization of Mal is also taken into account, it is seen that both monomers are in contact with TLR4, one of which has the interface residue at the correct site.

Mentions: Like the TLR4-homodimer, we predicted several architectures for the TLR4-Mal interaction. The two TLR4-dimers (BB and FF) use different interfaces to interact with Mal TIR-domain, suggesting that distinct TLR4-Mal architectures are possible (Fig. 4a,c). However, the previously suggested interface residues of Mal (R184, A185, & Y187)27 are not at the correct site. When we superimpose the Mal-homodimer on the TLR4-Mal complexes, we observed that both Mal monomers are in contact with TLR4 and one of the Mal monomers has the proposed interface residues at the correct site (Fig. 4b,d). This underscores the importance of higher order oligomerization modes while deciphering signaling pathways.


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)

Interaction models of Mal-monomer (a,c) and Mal-dimer (b,d) with BB and FF TLR4-homodimer models. Yellow protein is Mal and green spheres show the proposed interface residues of Mal (R184, A185, Y187)27, none of which are at the correct site in the monomeric-Mal-TLR interaction model. However, if dimerization of Mal is also taken into account, it is seen that both monomers are in contact with TLR4, one of which has the interface residue at the correct site.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Interaction models of Mal-monomer (a,c) and Mal-dimer (b,d) with BB and FF TLR4-homodimer models. Yellow protein is Mal and green spheres show the proposed interface residues of Mal (R184, A185, Y187)27, none of which are at the correct site in the monomeric-Mal-TLR interaction model. However, if dimerization of Mal is also taken into account, it is seen that both monomers are in contact with TLR4, one of which has the interface residue at the correct site.
Mentions: Like the TLR4-homodimer, we predicted several architectures for the TLR4-Mal interaction. The two TLR4-dimers (BB and FF) use different interfaces to interact with Mal TIR-domain, suggesting that distinct TLR4-Mal architectures are possible (Fig. 4a,c). However, the previously suggested interface residues of Mal (R184, A185, & Y187)27 are not at the correct site. When we superimpose the Mal-homodimer on the TLR4-Mal complexes, we observed that both Mal monomers are in contact with TLR4 and one of the Mal monomers has the proposed interface residues at the correct site (Fig. 4b,d). This underscores the importance of higher order oligomerization modes while deciphering signaling pathways.

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