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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

TLR4 homodimer models.(a) Back-to-back TLR4 dimer (BB). (b) Face-to-face TLR4 dimer (FF), which is very similar a previously suggested TLR4-dimer model21 and crystal structure of the dimeric TIR domain of IL-1RAPL (1t3g.pdb)42. (c) Another face-to-face dimer (FF2) in which BB-loops are in very close proximity. The box in the lower left corner shows the structural alignment of this TLR4-homodimer model with the one that is obtained by superimposition of TLR4 with TLR2 homodimer crystal structure (1o77_CD), (146 of 276 residues with 0.73 RMSD by multiport). Cyan color is TLR4 TIR domain, red-labeled regions are BB-loops, and yellow spheres are C747 residues on each TLR4 TIR domain, which are suggested to be involved in the interface. The dark blue dimer in the box is TLR4-dimer, which is obtained by superimposition with TLR2 dimer (1o77_CD).
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f3: TLR4 homodimer models.(a) Back-to-back TLR4 dimer (BB). (b) Face-to-face TLR4 dimer (FF), which is very similar a previously suggested TLR4-dimer model21 and crystal structure of the dimeric TIR domain of IL-1RAPL (1t3g.pdb)42. (c) Another face-to-face dimer (FF2) in which BB-loops are in very close proximity. The box in the lower left corner shows the structural alignment of this TLR4-homodimer model with the one that is obtained by superimposition of TLR4 with TLR2 homodimer crystal structure (1o77_CD), (146 of 276 residues with 0.73 RMSD by multiport). Cyan color is TLR4 TIR domain, red-labeled regions are BB-loops, and yellow spheres are C747 residues on each TLR4 TIR domain, which are suggested to be involved in the interface. The dark blue dimer in the box is TLR4-dimer, which is obtained by superimposition with TLR2 dimer (1o77_CD).

Mentions: Upon stimulation, TLRs form homo- or hetero-dimers with their Leucine Rich Repeats (LRRs) and TIR domains22. The structure of the TLR4 TIR-domain has not yet been resolved. We built its model by the I-TASSER server (residues 672-818)41. The crystal structure of the TLR1 TIR domain (PDB_ID: 1fyv) was used as the template. The model has 1.29 Å RMSD with TIR domains of other TLRs over 111 residues and other TLRs have 1.22 Å RMSD over 112 residues with each other. Several models have been proposed for the TLR4-TLR4 interaction based on mutagenesis212229 with disagreements among these with respect to interface residues2129. Such diverse findings for the interface region may suggest different binding modes for TLR4 dimerization. Also, the presence of other partners, like Mal, may change the TLR4 binding mode preference. In line with this idea, we found three different TLR4-homodimer organizations (Fig. 3). Details of the interactions are in Table S1.


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)

TLR4 homodimer models.(a) Back-to-back TLR4 dimer (BB). (b) Face-to-face TLR4 dimer (FF), which is very similar a previously suggested TLR4-dimer model21 and crystal structure of the dimeric TIR domain of IL-1RAPL (1t3g.pdb)42. (c) Another face-to-face dimer (FF2) in which BB-loops are in very close proximity. The box in the lower left corner shows the structural alignment of this TLR4-homodimer model with the one that is obtained by superimposition of TLR4 with TLR2 homodimer crystal structure (1o77_CD), (146 of 276 residues with 0.73 RMSD by multiport). Cyan color is TLR4 TIR domain, red-labeled regions are BB-loops, and yellow spheres are C747 residues on each TLR4 TIR domain, which are suggested to be involved in the interface. The dark blue dimer in the box is TLR4-dimer, which is obtained by superimposition with TLR2 dimer (1o77_CD).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: TLR4 homodimer models.(a) Back-to-back TLR4 dimer (BB). (b) Face-to-face TLR4 dimer (FF), which is very similar a previously suggested TLR4-dimer model21 and crystal structure of the dimeric TIR domain of IL-1RAPL (1t3g.pdb)42. (c) Another face-to-face dimer (FF2) in which BB-loops are in very close proximity. The box in the lower left corner shows the structural alignment of this TLR4-homodimer model with the one that is obtained by superimposition of TLR4 with TLR2 homodimer crystal structure (1o77_CD), (146 of 276 residues with 0.73 RMSD by multiport). Cyan color is TLR4 TIR domain, red-labeled regions are BB-loops, and yellow spheres are C747 residues on each TLR4 TIR domain, which are suggested to be involved in the interface. The dark blue dimer in the box is TLR4-dimer, which is obtained by superimposition with TLR2 dimer (1o77_CD).
Mentions: Upon stimulation, TLRs form homo- or hetero-dimers with their Leucine Rich Repeats (LRRs) and TIR domains22. The structure of the TLR4 TIR-domain has not yet been resolved. We built its model by the I-TASSER server (residues 672-818)41. The crystal structure of the TLR1 TIR domain (PDB_ID: 1fyv) was used as the template. The model has 1.29 Å RMSD with TIR domains of other TLRs over 111 residues and other TLRs have 1.22 Å RMSD over 112 residues with each other. Several models have been proposed for the TLR4-TLR4 interaction based on mutagenesis212229 with disagreements among these with respect to interface residues2129. Such diverse findings for the interface region may suggest different binding modes for TLR4 dimerization. Also, the presence of other partners, like Mal, may change the TLR4 binding mode preference. In line with this idea, we found three different TLR4-homodimer organizations (Fig. 3). Details of the interactions are in Table S1.

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