Toll-like receptors (TLRs) and receptors for pro-inflammatory cytokines IL-1 and IL-18 share a common TIR domain in their intracellular region and belong to the TLR/IL1-R superfamily. TLRs recognize pathogen-associated molecular patterns (PAMPs) to initiate protective immune responses. The molecular pathways for these receptors are complex and their dysregulation is associated with many human diseases both within and beyond the immune system. Signal transduction of these receptors is initiated by the approximation of the receptor TIR domains upon binding of PAMPs and cytokines. This leads to the recruitment of intracellular TIR- containing adaptors such as MyD88, TIRAP/Mal, TRIF and TRAM. MyD88 is critical for signaling responses of IL-1, IL-18, and all TLRs except TLR3. In addition to its C-terminal TIR domain, MyD88 contains an N-terminal death domain (DD). Through the DD, MyD88 interacts with IRAKs, including IRAK1, IRAK2, IRAK4 and IRAK-M, which are characterized by an N- terminal DD and a C-terminal Ser/Thr kinase or kinase-like domain. Eventually, the ensuing pathway activates transcription factors NF-kB, AP-1, and IRFs to elicit anti-pathogen responses and inflammation. Despite the biological importance of the TLR/IL-1R signaling system, limited structural and mechanistic information is available. In this application, we propose to assemble the membrane- proximal signaling complexes and to elucidate the molecular basis of this signal transduction.
Engagement of the TLR/IL-1R pathway in appropriate physiological contexts initiates the development of protective immune responses. However, the complexity of this pathway also renders itself susceptible to interruption and dysregulation, leading to its association with many human diseases. For example, inherited mutations or polymorphisms in TIR-adapters and IRAKs may cause either extreme sensitivity to or protection against infections. Other types of dysregulation in the pathway contribute to both diseases in the immune system such as inflammatory disorders, autoimmune diseases and allergy, and diseases beyond the immune system such as cancer, insulin resistance, atherosclerosis, and painful neuropathy.
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