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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

3D schematic view of TIR-domain signalosome, myddosome and TLR clustering.It is known that TLRs cluster on lipid rafts, but they cannot tetramerize due to the steric hindrance of their ectodomains2634. Oligomerization of the downstream proteins may hold TLRs together. Here, all TIR domains are in dimer form, TLR4, Mal, and MyD88. A TLR4-dimer recruits two Mal-dimers, which in turn recruit four MyD88-dimers. In the myddosome complexes, there are six MyD88 molecules, four IRAK4 and four IRAK2. The box at the upper right corner shows the cartoon version of the model. The PDB_ID of the myddosome complex is 3mop: MyD88 death domains 3mopBCDE, IRAK4 death domains 3mopGHIJ, IRAK2 death domains 3mopKLMN. Pink circles are PI(4,5)P2, which are enriched in lipid rafts and N-terminal region of Mal associates with it.
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f2: 3D schematic view of TIR-domain signalosome, myddosome and TLR clustering.It is known that TLRs cluster on lipid rafts, but they cannot tetramerize due to the steric hindrance of their ectodomains2634. Oligomerization of the downstream proteins may hold TLRs together. Here, all TIR domains are in dimer form, TLR4, Mal, and MyD88. A TLR4-dimer recruits two Mal-dimers, which in turn recruit four MyD88-dimers. In the myddosome complexes, there are six MyD88 molecules, four IRAK4 and four IRAK2. The box at the upper right corner shows the cartoon version of the model. The PDB_ID of the myddosome complex is 3mop: MyD88 death domains 3mopBCDE, IRAK4 death domains 3mopGHIJ, IRAK2 death domains 3mopKLMN. Pink circles are PI(4,5)P2, which are enriched in lipid rafts and N-terminal region of Mal associates with it.

Mentions: Mutagenesis studies identified interface residues and led to structural models of some of the binary interactions of TIR-domain signalosome682127293031 but not of the entire complex. Here, we model the MyD88- and TRIF-dependent signalosomes by exploiting the powerful PRISM algorithm3233. The architecture that we obtain provides the structural basis for TLR clustering through formation of a TIR-domain signalosome with 8 MyD88 molecules and a helical myddosome crystal structure with 6 MyD88 (Fig. 2). Our binary interactions are compatible with available experimental data. Significantly, our results reveal how regulation at key anti- and pro-inflammatory signaling checkpoints takes place, providing insight into TLR and MyD88 signaling decisions.


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)

3D schematic view of TIR-domain signalosome, myddosome and TLR clustering.It is known that TLRs cluster on lipid rafts, but they cannot tetramerize due to the steric hindrance of their ectodomains2634. Oligomerization of the downstream proteins may hold TLRs together. Here, all TIR domains are in dimer form, TLR4, Mal, and MyD88. A TLR4-dimer recruits two Mal-dimers, which in turn recruit four MyD88-dimers. In the myddosome complexes, there are six MyD88 molecules, four IRAK4 and four IRAK2. The box at the upper right corner shows the cartoon version of the model. The PDB_ID of the myddosome complex is 3mop: MyD88 death domains 3mopBCDE, IRAK4 death domains 3mopGHIJ, IRAK2 death domains 3mopKLMN. Pink circles are PI(4,5)P2, which are enriched in lipid rafts and N-terminal region of Mal associates with it.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: 3D schematic view of TIR-domain signalosome, myddosome and TLR clustering.It is known that TLRs cluster on lipid rafts, but they cannot tetramerize due to the steric hindrance of their ectodomains2634. Oligomerization of the downstream proteins may hold TLRs together. Here, all TIR domains are in dimer form, TLR4, Mal, and MyD88. A TLR4-dimer recruits two Mal-dimers, which in turn recruit four MyD88-dimers. In the myddosome complexes, there are six MyD88 molecules, four IRAK4 and four IRAK2. The box at the upper right corner shows the cartoon version of the model. The PDB_ID of the myddosome complex is 3mop: MyD88 death domains 3mopBCDE, IRAK4 death domains 3mopGHIJ, IRAK2 death domains 3mopKLMN. Pink circles are PI(4,5)P2, which are enriched in lipid rafts and N-terminal region of Mal associates with it.
Mentions: Mutagenesis studies identified interface residues and led to structural models of some of the binary interactions of TIR-domain signalosome682127293031 but not of the entire complex. Here, we model the MyD88- and TRIF-dependent signalosomes by exploiting the powerful PRISM algorithm3233. The architecture that we obtain provides the structural basis for TLR clustering through formation of a TIR-domain signalosome with 8 MyD88 molecules and a helical myddosome crystal structure with 6 MyD88 (Fig. 2). Our binary interactions are compatible with available experimental data. Significantly, our results reveal how regulation at key anti- and pro-inflammatory signaling checkpoints takes place, providing insight into TLR and MyD88 signaling decisions.

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