title: The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway.
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.
authors: Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.|Center for Computational Biology and Bioinformatics, Koc University, Istanbul, Turkey.
authors: Emine
authors: E
authors: Guven-Maiorov
authors: Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.|Center for Computational Biology and Bioinformatics, Koc University, Istanbul, Turkey.
authors: Ozlem
authors: O
authors: Keskin
authors: Center for Computational Biology and Bioinformatics, Koc University, Istanbul, Turkey.|Department of Computer Engineering, Koc University, Istanbul, Turkey.
authors: Attila
authors: A
authors: Gursoy
authors: Clinical Genomic Unit, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors: Carter
authors: C
authors: VanWaes
authors: Clinical Genomic Unit, Head and Neck Surgery Branch, National Institute on Deafness and Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors: Zhong
authors: Z
authors: Chen
authors: Cancer and Inflammation Program, Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
authors: Chung-Jung
authors: CJ
authors: Tsai
authors: Cancer and Inflammation Program, Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.|Sackler Inst. of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors: Ruth
authors: R
authors: Nussinov
mesh_terms: D006801:Humans; D021621:Imaging, Three-Dimensional; D008954:Models, Biological; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4