Abstract
Toll-like receptor 3 (TLR3) provides the host with antiviral defense by initiating an immune signaling cascade for the production of type I interferons. The X-ray structures of isolated TLR3 ectodomain (ECD) and transmembrane (TM) domains have been reported; however, the structure of a membrane-solvated, full-length receptor remains elusive. We investigated an all-residue TLR3 model embedded inside a phospholipid bilayer using molecular dynamics simulations. The TLR3-ECD exhibited a ~30°–35° tilt on the membrane due to the electrostatic interaction between the N-terminal subdomain and phospholipid headgroups. Although the movement of dsRNA did not affect the dimer integrity of TLR3, its sugar-phosphate backbone was slightly distorted with the orientation of the ECD. TM helices exhibited a noticeable tilt and curvature but maintained a consistent crossing angle, avoiding the hydrophobic mismatch with the bilayer. Residues from the αD helix and the CD and DE loops of the Toll/interleukin-1 receptor (TIR) domains were partially absorbed into the lower leaflet of the bilayer. We found that the previously unknown TLR3-TIR dimerization interface could be stabilized by the reciprocal contact between αC and αD helices of one subunit and the αC helix and the BB loop of the other. Overall, the present study can be helpful to understand the signaling-competent form of TLR3 in physiological environments.
Highlights
Toll-like receptor 3 (TLR3) is an important pattern recognition receptor that recognizes double-stranded RNA, which is a viral replication intermediate [1], and its synthetic analog polyinosinic:polycytidylic acid [2]
TLR3 is predominantly expressed in the endosomal compartment of sentinel cells such as macrophages and myeloid dendritic cells, where the recognition of endocytosed double-stranded RNA (dsRNA) occurs at an acidic pH [3,4]
To establish a molecular basis for the complete structural organization of TLR3, we constructed three separate models of the full-length TLR3-dsRNA homodimerization complex and simulated them in POPC bilayers for a duration of 200 ns
Summary
Toll-like receptor 3 (TLR3) is an important pattern recognition receptor that recognizes double-stranded RNA (dsRNA), which is a viral replication intermediate [1], and its synthetic analog polyinosinic:polycytidylic acid [2]. DsRNA-mediated TLR3 signaling leads to the activation of a number of transcription factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), IRF-7, and members of the activator protein 1 (AP-1) family [8]. Because TLR3 triggers a strong immune response against viral infection, it is considered a promising drug target for the development of effective vaccine adjuvants [13]. Liu et al (2008) have proposed a full-length model of TLR3 [10]; the atomistic details of inter-domain interactions, time-dependent structural evolution, and dynamics of TM, TIR, and ECD with respect to the phospholipid bilayer as a single unit have not been thoroughly studied. The ECD and TIR domains are established drug targets; a detailed knowledge about their structural topology and intermolecular interactions is crucial for the development of effective, novel adjuvant, or antagonistic candidates
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