Abstract
Toll-like receptor 3 (TLR3), an endosomal receptor crucial for immune responses upon viral invasion. The TLR3 ectodomain (ECD) is responsible for double-stranded RNA (dsRNA) recognition and mutational analysis suggested that TLR3 ECD C-terminal dimerization is essential for dsRNA binding. Moreover, the L412F polymorphism of TLR3 is associated with human diseases. Although the mouse structure of the TLR3-dsRNA complex provides valuable insights, the structural dynamic behavior of the TLR3-dsRNA complex in humans is not completely understood. Hence, in this study, we performed molecular dynamic simulations of human wild-type and mutant TLR3 complexes. Our results suggested that apoTLR3 ECD dimers are unlikely to be stable due to the distance between the monomers are largely varied during simulations. The observed interaction energies and hydrogen bonds in dsRNA-bound TLR3 wild-type and mutant complexes indicate the presence of a weak dimer interface at the TLR3 ECD C-terminal site, which is required for effective dsRNA binding. The L412F mutant exhibited similar dominant motion compared to wild-type. Additionally, we identified the distribution of crucial residues for signal propagation in TLR3-dsRNA complex through the evaluation of residue betweenness centrality (CB). The results of this study extend our understanding of TLR3-dsRNA complex, which may assist in TLR3 therapeutics.
Highlights
Toll-like receptor 3 (TLR3), an endosomal receptor crucial for immune responses upon viral invasion
The correlation between the root mean square fluctuations (RMSF) values for the two chains was less in dTLR3WT-double-stranded RNA (dsRNA) compared to other complexes, this is due to high fluctuations were observed at the N-terminal region for first few residues. apo_dTLR3WT showed a larger correlation coefficient than that of dsRNA bound complexes (Supplementary Fig. S2)
The human TLR3 ECD is found in a monomeric state, whereas the mouse TLR3 structure is in a dsRNA-bound TLR3 dimeric state where the major interaction site for the dsRNA and C-terminal dimer interface is found in the TLR3 ectodomain
Summary
Toll-like receptor 3 (TLR3), an endosomal receptor crucial for immune responses upon viral invasion. The observed interaction energies and hydrogen bonds in dsRNA-bound TLR3 wild-type and mutant complexes indicate the presence of a weak dimer interface at the TLR3 ECD C-terminal site, which is required for effective dsRNA binding. The dsRNAs of longer than 30 bp are candidates to induce innate immune responses to curb viral infection[22] and protein crystallography studies have shown that mouse TLR3 binds to 46-bp dsRNA23. The N-terminal interaction site includes the LRR-NT and 1–3 LRR components, consisting of His[39], His[60], Gln[62], Arg[64], Phe[84], His[108], Glu[110], and Ser[112] (identical interacting residues from mice and humans are given). Further mutational analysis of human TLR3 has revealed that His[39], His[60], His[108], His[539], and Asn[541] residues interact with dsRNA, and the C-terminal dimerization site is critical for dsRNA binding as well as TLR3 signaling[24] (Fig. 1)
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