Home LiteratureArticle Details
PMID: 16720699 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

The dsRNA binding site of human Toll-like receptor 3.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 23 ·2006-06-06 ·Pages 8792-7

Bell JK, Askins J, Hall PR, Davies DR, Segal DM

Abstract

Pathogen recognition by Toll-like receptors (TLRs) initiates innate immune responses that are essential for inhibiting pathogen dissemination and for the development of acquired immunity. The TLRs recognize pathogens with their N-terminal ectodomains (ECD), but the molecular basis for this recognition is not known. Recently we reported the x-ray structure for unliganded TLR3-ECD; however, it has proven difficult to obtain a crystal structure of TLR3 with its ligand, dsRNA. We have now located the TLR3 ligand binding site by mutational analysis. More than 50 single-residue mutations have been generated throughout the TLR3-ECD, but only two, H539E and N541A, resulted in the loss of TLR3 activation and ligand binding functions. These mutations locate the dsRNA binding site on the glycan-free, lateral surface of TLR3 toward the C terminus and suggest a model for dsRNA binding and TLR3 activation.

MeSH Terms
Binding Sites Humans Leucine-Rich Repeat Proteins Ligands Models, Molecular Mutation/genetics Nucleic Acid Conformation Protein Conformation Proteins/genetics RNA, Double-Stranded/chemistry,genetics,metabolism RNA-Binding Proteins/chemistry,genetics,metabolism Signal Transduction Sulfates/metabolism Toll-Like Receptor 3/chemistry,genetics,metabolism
Chemicals
Leucine-Rich Repeat Proteins Ligands Proteins RNA, Double-Stranded RNA-Binding Proteins Sulfates Toll-Like Receptor 3
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Bell Jessica K
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, and Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Askins Janine
Hall Pamela R
Davies David R
Segal David M
References (27)
27 references, click to expand
  1. TLR3-, TLR7-, and TLR9-mediated production of proinflammatory cytokines and chemokines from murine connective tissue type skin-derived mast cells but not from bone marrow-derived mast cells.
    J Immunol. 2004 Jul 1;173(1):531-41 PMID: 15210814
  2. APC-independent activation of NK cells by the Toll-like receptor 3 agonist double-stranded RNA.
    J Immunol. 2004 Jan 1;172(1):138-43 PMID: 14688319
  3. CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells.
    Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10116-21 PMID: 15218108
  4. Four N-linked glycosylation sites in human toll-like receptor 2 cooperate to direct efficient biosynthesis and secretion.
    J Biol Chem. 2004 Aug 13;279(33):34589-94 PMID: 15173186
  5. A complex of soluble MD-2 and lipopolysaccharide serves as an activating ligand for Toll-like receptor 4.
    J Biol Chem. 2004 Aug 13;279(33):34698-704 PMID: 15175334
  6. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.
    Science. 1998 Dec 11;282(5396):2085-8 PMID: 9851930
  7. Molecular basis of double-stranded RNA-protein interactions: structure of a dsRNA-binding domain complexed with dsRNA.
    EMBO J. 1998 Dec 15;17(24):7505-13 PMID: 9857205
  8. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4.
    J Exp Med. 1999 Jun 7;189(11):1777-82 PMID: 10359581
  9. p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells.
    Blood. 2004 Dec 15;104(13):4157-64 PMID: 15315972
  10. The double-stranded RNA-binding motif, a versatile macromolecular docking platform.
    FEBS J. 2005 May;272(9):2109-17 PMID: 15853796
  11. Crystal structure of human toll-like receptor 3 (TLR3) ectodomain.
    Science. 2005 Jul 22;309(5734):581-5 PMID: 15961631
  12. The molecular structure of the Toll-like receptor 3 ligand-binding domain.
    Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10976-80 PMID: 16043704
  13. TLR3 in antiviral immunity: key player or bystander?
    Trends Immunol. 2005 Sep;26(9):462-8 PMID: 16027039
  14. Recognition of double-stranded RNA by human toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH.
    J Biol Chem. 2005 Nov 18;280(46):38133-45 PMID: 16144834
  15. Pathogen recognition and innate immunity.
    Cell. 2006 Feb 24;124(4):783-801 PMID: 16497588
  16. Structural and functional analyses of the human Toll-like receptor 3. Role of glycosylation.
    J Biol Chem. 2006 Apr 21;281(16):11144-51 PMID: 16533755
  17. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains.
    Nature. 2000 Nov 2;408(6808):111-5 PMID: 11081518
  18. Regulation of Toll-like receptors in human monocytes and dendritic cells.
    J Immunol. 2001 Jan 1;166(1):249-55 PMID: 11123299
  19. Intracellular functions of N-linked glycans.
    Science. 2001 Mar 23;291(5512):2364-9 PMID: 11269317
  20. How the immune system works to protect the host from infection: a personal view.
    Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7461-8 PMID: 11390983
  21. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.
    Nature. 2001 Oct 18;413(6857):732-8 PMID: 11607032
  22. Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling.
    Biochem Biophys Res Commun. 2002 May 24;293(5):1364-9 PMID: 12054664
  23. An extensively associated dimer in the structure of the C713S mutant of the TIR domain of human TLR2.
    Biochem Biophys Res Commun. 2002 Nov 29;299(2):216-21 PMID: 12437972
  24. The role of disulfide bonds in the assembly and function of MD-2.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3919-24 PMID: 12642668
  25. Subcellular localization of Toll-like receptor 3 in human dendritic cells.
    J Immunol. 2003 Sep 15;171(6):3154-62 PMID: 12960343
  26. Leucine-rich repeats and pathogen recognition in Toll-like receptors.
    Trends Immunol. 2003 Oct;24(10):528-33 PMID: 14552836
  27. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3.
    J Allergy Clin Immunol. 2004 Jul;114(1):174-82 PMID: 15241362
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0603245103
Published
2006-06-06
Epub
2006-00-23
Pages
8792-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1482657
Subset
IM
Grants
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1073/pnas.0603245103 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2