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 allresidue 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.
Original language | English |
---|---|
Article number | 2857 |
Journal | International Journal of Molecular Sciences |
Volume | 21 |
Issue number | 8 |
DOIs | |
State | Published - Apr 1 2020 |
Externally published | Yes |
Funding
Funding: This work was supported by the National Research Foundation of Korea (NRF-2019M3A9A8065098, 2019M3D1A1078940 and 2019R1A6A1A11051471). This research was also supported by a grant of the Daegu-Gyeongbuk/Osong Medical Cluster R&D Project funded by the Ministry of Science and ICT; by the Ministry of Trade, Industry, and Energy; and by the Ministry of Health and Welfare, Republic of Korea (HI19C0760). This work was supported by the National Research Foundation of Korea (NRF-2019M3A9A8065098, 2019M3D1A1078940 and 2019R1A6A1A11051471). This research was also supported by a grant of the Daegu- Gyeongbuk/Osong Medical Cluster R&D Project funded by the Ministry of Science and ICT; by the Ministry of Trade, Industry, and Energy; and by the Ministry of Health and Welfare, Republic of Korea (HI19C0760).
Keywords
- Molecular dynamics simulation
- Phospholipid bilayer
- Toll-like receptor 3