@article{8efe2ede5fec40d3b5142d6a9f2c69c5,
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.",
author = "Emine Guven-Maiorov and Ozlem Keskin and Attila Gursoy and Carter VanWaes and Zhong Chen and Tsai, {Chung Jung} and Ruth Nussinov",
note = "Funding Information: We acknowledge the funds from TUBITAK projects (in part) (Project No: 114M196 and 113E164). OK and AG are the members of Science Academy, Turkey. ܀is project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. ܀is research was supported (in part) by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. ?e content of this publication does not necessarily re ᠀ecthe views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. ܀is research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.",
year = "2015",
month = aug,
day = "21",
doi = "10.1038/srep13128",
language = "אנגלית",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
}