Abstract
Toll-like receptors (TLRs) are a unique category of pattern recognition receptors that recognize distinct pathogenic components, often utilizing the same set of downstream adaptors. Specific molecular features of extracellular, transmembrane (TM), and cytoplasmic domains of TLRs are crucial for coordinating the complex, innate immune signaling pathway. Here, we constructed a full-length structural model of TLR4—a widely studied member of the interleukin-1 receptor/TLR superfamily—using homology modeling, protein–protein docking, and molecular dynamics simulations to understand the differential domain organization of TLR4 in a membrane-aqueous environment. Results showed that each functional domain of the membrane-bound TLR4 displayed several structural transitions that are biophysically essential for plasma membrane integration. Specifically, the extracellular and cytoplasmic domains were partially immersed in the upper and lower leaflets of the membrane bilayer. Meanwhile, TM domains tilted considerably to overcome the hydrophobic mismatch with the bilayer core. Our analysis indicates an alternate dimerization or a potential oligomerization interface of TLR4-TM. Moreover, the helical properties of an isolated TM dimer partly agree with that of the full-length receptor. Furthermore, membrane-absorbed or solvent-exposed surfaces of the toll/interleukin-1 receptor domain are consistent with previous X-ray crystallography and biochemical studies. Collectively, we provided a complete structural model of membrane-bound TLR4 that strengthens our current understanding of the complex mechanism of receptor activation and adaptor recruitment in the innate immune signaling pathway.
Highlights
Toll-like receptors (TLRs) are key components of the vertebrate innate immune system and play a dominant role in the activation of the adaptive immune system [1,2,3]
TLR4-extracellular ligand binding domain (ECD) of simulation 2 showed a similar behavior to simulation 1 by inclining over the membrane, where the leucinerich repeats (LRR)-NT was completely buried inside the phospholipid headgroups (Figures 1C,D)
We found that the opening of the TAK-242 binding cavity was lined with several bulkier amino acids, namely Y751, R780, L778, H740, and Q782, that partially blocked the cavity opening in both full-length TLR4 models (Figures 6A,B)
Summary
Toll-like receptors (TLRs) are key components of the vertebrate innate immune system and play a dominant role in the activation of the adaptive immune system [1,2,3]. They are pattern recognition receptors that recognize exogenous pathogen-associated molecular patterns or endogenous damageassociated molecular patterns to initiate a complex cascade of signal transduction to produce proinflammatory cytokines and interferons (IFNs) [4]. Ligand-induced TLR dimerization results in the recruitment of the downstream adaptor, myeloid differentiation primary response gene 88 (MyD88), or in the case of TLR3, toll/ interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon β (TRIF). Activated NF-κB and IRF3 translocate to the nucleus and assist in the transcription of pro-inflammatory cytokines: interleukin-1 (IL-1), IL-6, IL-10, IFN1β, and IFNγ [22]
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