Intracellular TLR Signaling: A Structural Perspective on Human Disease

Abstract

TLRs are crucial sensors of microbial infection. Maintaining structural integrity of TLR signaling components is essential for subsequent immunological protection. Alterations to the structure of these signaling molecules are often associated with profound clinical outcomes and susceptibility to various infectious diseases. These changes in structure are sometimes the result of a single nucleotide polymorphism (SNP). Numerous SNPs have been found in components of the TLR signaling pathway. Recently, the medical consequences and effects on TLR signaling of several of these SNPs have been elucidated. In addition, there have been numerous structures solved that are important to our understanding of the TLR signaling pathway at the molecular level. The scope of this review is to tie together current structural, biochemical, and genetic information of TLR signaling.

Toll-like receptor 4 signaling pathway can be triggered by grass carp reovirus and Aeromonas hydrophila infection in rare minnow Gobiocypris rarus

“…TLRs recognize microbial structures (from gram-positive and gram-negative bacteria, mycobacteria, RNA and DNA viruses, fungi and protozoans) in the earliest phase of the host defence response, and induce hundreds of host genes through a complex network of signaling that allows for an appropriate response for eliminating the invading pathogen [19,20]. TLRs are comprised of an ectodomain with LRRs, a transmembrane region, and a cytoplasmic TIR domain.…”

“…LRRs form a single continuous structure and adopt an arc or horseshoe shape, and have been inferred to be responsible for molecular recognition [21]. Upon receptor activation, it is believed that a TIR domain signaling complex is formed between the receptor and the adaptor TIR domains in order for signal transduction to occur [20].…”

Characterization of a TIR-like protein from Paracoccus denitrificans

“…Mammalian cells use the TLR class, containing a single transmembrane spanning region, to bind to pathogen associated molecular patterns (PAMP), like lipopolysaccharides from Gram negative bacteria. Using the receptor's intracellular Toll-like/IL-1 receptor/plant Resistance (TIR) domain, the activated receptor recruits a family of cytoplasmic TIR containing proteins known as the adaptors to induce a cascade of signal transduction ultimately leading to the activation of the transcription factor NFκB [3,4]. As a result, genes involved in organizing an inflammatory response against bacterial infection like TNF-α or interferon-β are switch on.…”

Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways

“…The molecular chaperone Hsp90 can lead to the phosphorylation of the intracellular tyrosine-kinase by binding to the extracellular domain of ErbB2 receptor, and then activating downstream PI3K/Akt and ERK1/2 pathways. TLR-4 is comprised of an ectodomain with leucine-rich repeats, a transmembrane region, and a cytoplasmic Toll/IL-1R (TIR) domain so named for its homology to the IL-1R (Lasker and Nair, 2006). It has been reported that TLR-4 agonists can strongly induce nuclear factor (NF)-κB activation and NO production in microglia (Jung et al, 2005).…”