A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer
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-solv...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/8/2857 |
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| author | Mahesh Chandra Patra Maria Batool Muhammad Haseeb Sangdun Choi |
| author_facet | Mahesh Chandra Patra Maria Batool Muhammad Haseeb Sangdun Choi |
| author_sort | Mahesh Chandra Patra |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T20:22:36Z |
| format | Article |
| id | doaj.art-c81423872fd24c1a86296893b6781fb3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T20:22:36Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c81423872fd24c1a86296893b6781fb32023-11-19T22:07:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01218285710.3390/ijms21082857A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid BilayerMahesh Chandra Patra0Maria Batool1Muhammad Haseeb2Sangdun Choi3Department of Molecular Science and Technology, Ajou University, Suwon 16499, KoreaDepartment of Molecular Science and Technology, Ajou University, Suwon 16499, KoreaDepartment of Molecular Science and Technology, Ajou University, Suwon 16499, KoreaDepartment of Molecular Science and Technology, Ajou University, Suwon 16499, KoreaToll-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.https://www.mdpi.com/1422-0067/21/8/2857Toll-like receptor 3molecular dynamics simulationphospholipid bilayer |
| spellingShingle | Mahesh Chandra Patra Maria Batool Muhammad Haseeb Sangdun Choi A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer International Journal of Molecular Sciences Toll-like receptor 3 molecular dynamics simulation phospholipid bilayer |
| title | A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer |
| title_full | A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer |
| title_fullStr | A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer |
| title_full_unstemmed | A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer |
| title_short | A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer |
| title_sort | computational probe into the structure and dynamics of the full length toll like receptor 3 in a phospholipid bilayer |
| topic | Toll-like receptor 3 molecular dynamics simulation phospholipid bilayer |
| url | https://www.mdpi.com/1422-0067/21/8/2857 |
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