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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

Possible TIR domain signalosome models for FF TLR4-dimer.(a) Interaction model of monomeric-MyD88 with TLR4 and Mal dimers. (b,c) MyD88-dependent TIR-domain signalosome models for FF TLR4-dimer. All proteins are in dimer form, including TLR4, Mal, and MyD88. It is known that dimeric MyD88 has higher affinity to stimulated TLRs due to their extended interfaces. In line with this, models (b,c) show that the second MyD88 of the MyD88-dimer is very close to TLR4. Especially in part-c, one of the MyD88 molecules in the dimer is bound to Mal, and the other is bound to TLR4. We obtained these complexes by superimposition of the binary interaction models of TLR4-TLR4, TLR4-Mal, Mal-Mal, Mal-MyD88 and MyD88-MyD88.
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f5: Possible TIR domain signalosome models for FF TLR4-dimer.(a) Interaction model of monomeric-MyD88 with TLR4 and Mal dimers. (b,c) MyD88-dependent TIR-domain signalosome models for FF TLR4-dimer. All proteins are in dimer form, including TLR4, Mal, and MyD88. It is known that dimeric MyD88 has higher affinity to stimulated TLRs due to their extended interfaces. In line with this, models (b,c) show that the second MyD88 of the MyD88-dimer is very close to TLR4. Especially in part-c, one of the MyD88 molecules in the dimer is bound to Mal, and the other is bound to TLR4. We obtained these complexes by superimposition of the binary interaction models of TLR4-TLR4, TLR4-Mal, Mal-Mal, Mal-MyD88 and MyD88-MyD88.

Mentions: Mal serves as a bridge between TLR4 and MyD88. Mutational analysis indicated that MyD88 R196 and R288 are at the Mal-MyD88 interface630. However, these two residues fall on opposite sides of MyD88, indicating that there is more than one bound conformation for the Mal-MyD88. Among several Mal-MyD88 architectures, only one features TLR4- and Mal-homodimers with R196 at the interface (Supplementary Figure S1), when superimposed with TLR4-Mal interactions. Figure 5a and Supplementary Fig. S2 show the signalosomes of TLR4-Mal-MyD88 for the two possible TLR4-homodimers, FF and BB, respectively. As in TLR4-Mal interaction where the suggested interface residues are at the correct site only when Mal is in dimer form, R288 of MyD88 is in contact with TLR4 only if MyD88 dimerizes (Fig. 5b and Supplementary Figure S3).


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)

Possible TIR domain signalosome models for FF TLR4-dimer.(a) Interaction model of monomeric-MyD88 with TLR4 and Mal dimers. (b,c) MyD88-dependent TIR-domain signalosome models for FF TLR4-dimer. All proteins are in dimer form, including TLR4, Mal, and MyD88. It is known that dimeric MyD88 has higher affinity to stimulated TLRs due to their extended interfaces. In line with this, models (b,c) show that the second MyD88 of the MyD88-dimer is very close to TLR4. Especially in part-c, one of the MyD88 molecules in the dimer is bound to Mal, and the other is bound to TLR4. We obtained these complexes by superimposition of the binary interaction models of TLR4-TLR4, TLR4-Mal, Mal-Mal, Mal-MyD88 and MyD88-MyD88.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Possible TIR domain signalosome models for FF TLR4-dimer.(a) Interaction model of monomeric-MyD88 with TLR4 and Mal dimers. (b,c) MyD88-dependent TIR-domain signalosome models for FF TLR4-dimer. All proteins are in dimer form, including TLR4, Mal, and MyD88. It is known that dimeric MyD88 has higher affinity to stimulated TLRs due to their extended interfaces. In line with this, models (b,c) show that the second MyD88 of the MyD88-dimer is very close to TLR4. Especially in part-c, one of the MyD88 molecules in the dimer is bound to Mal, and the other is bound to TLR4. We obtained these complexes by superimposition of the binary interaction models of TLR4-TLR4, TLR4-Mal, Mal-Mal, Mal-MyD88 and MyD88-MyD88.
Mentions: Mal serves as a bridge between TLR4 and MyD88. Mutational analysis indicated that MyD88 R196 and R288 are at the Mal-MyD88 interface630. However, these two residues fall on opposite sides of MyD88, indicating that there is more than one bound conformation for the Mal-MyD88. Among several Mal-MyD88 architectures, only one features TLR4- and Mal-homodimers with R196 at the interface (Supplementary Figure S1), when superimposed with TLR4-Mal interactions. Figure 5a and Supplementary Fig. S2 show the signalosomes of TLR4-Mal-MyD88 for the two possible TLR4-homodimers, FF and BB, respectively. As in TLR4-Mal interaction where the suggested interface residues are at the correct site only when Mal is in dimer form, R288 of MyD88 is in contact with TLR4 only if MyD88 dimerizes (Fig. 5b and Supplementary Figure S3).

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