DOI: 10.1073/pnas.0505077102. The molecular structure of the Toll-like receptor 3 ligand-binding domain

The molecular structure of the Toll-like receptor 3 ligand-binding domain

10.1073/pnas.0505077102

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Innate immunity is the first line of defense against invading pathogens. Toll-like receptors (TLRs) act as sentinels of the innate immune system, sensing a variety of ligands from lipopolysaccharide to flagellin to dsRNA through their ligand-binding domain that is composed of leucine-rich repeats (LRRs). Ligand binding initiates a signaling cascade that leads to the up-regulation of inflammation mediators. In this study, we have expressed and crystallized the ectodomain (ECD) of human TLR3, which recognizes dsRNA, a molecular signature of viruses, and have determined the molecular structure to 2.4-Å resolution. The overall horseshoe-shaped structure of the TLR3-ECD is formed by 23 repeating LRRs that are capped at each end by specialized non-LRR domains. The extensive β-sheet on the molecule's concave surface forms a platform for several modifications, including insertions in the LRRs and 11 N -linked glycans. The TLR3-ECD structure indicates how LRR loops can establish distinct pathogen recognition receptors.

Bibliography

Bell, J. K., Botos, I., Hall, P. R., Askins, J., Shiloach, J., Segal, D. M., & Davies, D. R. (2005). The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proceedings of the National Academy of Sciences, 102(31), 10976â10980.

Authors 7

Jessica K. Bell (first)
Istvan Botos (additional)
Pamela R. Hall (additional)
Janine Askins (additional)
Joseph Shiloach (additional)
David M. Segal (additional)
David R. Davies (additional)

References 43 Referenced 299

10.1146/annurev.immunol.21.120601.141126
10.1093/intimm/dxh186
10.1016/S0092-8674(00)80172-5
Beutler, B. & Rehli, M. (2002) Curr. Top. Microbiol. Immunol. 270, 1-21.12467241 / Curr. Top. Microbiol. Immunol. (2002)
10.1038/nri1391
10.1038/ni1112
10.1126/science.282.5396.2085
10.1038/35074106
10.1038/35099560
10.1016/S1471-4906(03)00242-4
10.1074/jbc.M403434200
10.1038/35040600
10.1110/ps.4010102
10.1016/j.molimm.2004.11.007
10.4049/jimmunol.171.6.3154
10.1038/nature03326
10.4049/jimmunol.169.12.6668
10.1107/S002188989801053X
Sun, P. D., Radaev, S. & Kattah, M. (2000) Acta Crystallogr. D 58, 1092-1098. / Acta Crystallogr. D (2000)
Otwinowski, Z. & Minor, W. (1997) Methods Enzymol. 276, 306-326. / Methods Enzymol. (1997)
10.1016/S0076-6879(97)76073-7
10.1016/S0076-6879(03)74002-6
10.1107/S0108767390010224
10.1107/S0907444994003112
10.1107/S0907444998003254
10.1107/S0021889892009944
10.1002/prot.10286
10.1016/0263-7855(96)00009-4
Christopher J. A. (1998) spock (Center for Macromolecular Design Texas A&M University College Station TX).
10.1002/prot.340110407
10.1126/science.273.5275.595
10.1126/science.107355
10.1016/S0092-8674(02)01136-4
10.1006/jmbi.2001.4973
10.1016/S0896-6273(03)00232-0
10.1023/B:GLYC.0000046275.28315.87
10.1016/S0959-440X(01)00266-4
10.4049/jimmunol.172.11.6545
10.1074/jbc.M310175200
10.1021/bi9912793
10.1126/science.1549776
10.1016/S0167-4889(02)00316-6
10.1126/science 1115253

Dates

Type	When
Created	20 years, 1 month ago (July 25, 2005, 8:49 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 2:17 p.m.)
Indexed	2 months, 2 weeks ago (June 17, 2025, 12:55 a.m.)
Issued	20 years, 1 month ago (July 25, 2005)
Published	20 years, 1 month ago (July 25, 2005)
Published Online	20 years, 1 month ago (July 25, 2005)
Published Print	20 years, 1 month ago (Aug. 2, 2005)

Funders 0

None

BibTeX

@article{Bell_2005, title={The molecular structure of the Toll-like receptor 3 ligand-binding domain}, volume={102}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0505077102}, DOI={10.1073/pnas.0505077102}, number={31}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Bell, Jessica K. and Botos, Istvan and Hall, Pamela R. and Askins, Janine and Shiloach, Joseph and Segal, David M. and Davies, David R.}, year={2005}, month=jul, pages={10976–10980} }

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  "abstract": "<jats:p>\n            Innate immunity is the first line of defense against invading pathogens. Toll-like receptors (TLRs) act as sentinels of the innate immune system, sensing a variety of ligands from lipopolysaccharide to flagellin to dsRNA through their ligand-binding domain that is composed of leucine-rich repeats (LRRs). Ligand binding initiates a signaling cascade that leads to the up-regulation of inflammation mediators. In this study, we have expressed and crystallized the ectodomain (ECD) of human TLR3, which recognizes dsRNA, a molecular signature of viruses, and have determined the molecular structure to 2.4-\u00c5 resolution. The overall horseshoe-shaped structure of the TLR3-ECD is formed by 23 repeating LRRs that are capped at each end by specialized non-LRR domains. The extensive \u03b2-sheet on the molecule's concave surface forms a platform for several modifications, including insertions in the LRRs and 11\n            <jats:italic>N</jats:italic>\n            -linked glycans. The TLR3-ECD structure indicates how LRR loops can establish distinct pathogen recognition receptors.\n          </jats:p>",
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