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Journal of immunology (Baltimore, Md. : 1950)2008; 181(2); 1245-1254; doi: 10.4049/jimmunol.181.2.1245

Elucidation of the MD-2/TLR4 interface required for signaling by lipid IVa.

Abstract: LPS signals through a membrane bound-complex of the lipid binding protein MD-2 and the receptor TLR4. In this study we identify discrete regions in both MD-2 and TLR4 that are required for signaling by lipid IVa, an LPS derivative that is an agonist in horse but an antagonist in humans. We show that changes in the electrostatic surface potential of both MD-2 and TLR4 are required in order that lipid IVa can induce signaling. In MD-2, replacing horse residues 57-66 and 82-89 with the equivalent human residues confers a level of constitutive activity on horse MD-2, suggesting that conformational switching in this protein is likely to be important in ligand-induced activation of MD-2/TLR4. We identify leucine-rich repeat 14 in the C terminus of TLR4 as essential for lipid IVa activation of MD-2/TLR4. Remarkably, we identify a single residue in the glycan-free flank of the horse TLR4 solenoid that confers the ability to signal in response to lipid IVa. These results suggest a mechanism of signaling that involves crosslinking mediated by both MD-2-receptor and receptor-receptor contacts in a model that shows striking similarities to the recently published structure (Cell 130: 1071-1082) of the ligand-bound TLR1/2 ectodomain heterodimer.
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Publication Date: 2008-07-09 PubMed ID: 18606678DOI: 10.4049/jimmunol.181.2.1245Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research investigates how the signaling mechanism between MD-2, a lipid-binding protein, and TLR4, a receptor in the immune system, is affected by lipid IVa, a derivative of LPS (a compound found in bacterial cell walls). It pinpoints specific areas in MD-2 and TLR4 necessary for signaling, and suggests a signaling model involving contact between multiple receptors.

Understanding MD-2/TLR4 and Lipid IVa

  • The research focuses on the interaction between two proteins, MD-2 and TLR4. These proteins function together on the cell surface and play a crucial role in the body’s immune response.
  • Lipid IVa, a derivative of LPS (lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria), plays a dual role in this domain. It acts as an agonist (activator) in horses but as an antagonist (blocker) in humans.

Key Findings with MD-2 and TLR4

  • The research identifies specific regions in both MD-2 and TLR4 that are necessary for signaling by lipid IVa. Certain changes in the electrostatic surface potential of both MD-2 and TLR4 are required for lipid IVa to induce signaling.
  • In MD-2, replacing certain horse residue sequences with the equivalent human residue sequences confers a level of self-activity, suggesting significant conformational switching in MD-2 is likely involved in activation of the MD-2/TLR4 complex by ligands (molecules that bind to another molecule).

Significance in TLR4 and Signaling Mechanism

  • The leucine-rich repeat 14 in the C terminus (the end part) of TLR4 is found essential for lipid IVa activation of the MD-2/TLR4 complex. A single residue in the glycan-free flank of the horse TLR4 solenoid was found to confer the ability to signal in response to lipid IVa.
  • These results suggest a mechanism of signaling that involves the crosslinking mediated by contacts between both MD-2 and its receptor, as well as between multiple receptors.
  • In terms of broader biological functions, this signaling model shows remarkable similarities to the structure of the ligand-bound TLR1/2 ectodomain heterodimer, another protein complex crucial in cellular communication.

Cite This Article

APA
Walsh C, Gangloff M, Monie T, Smyth T, Wei B, McKinley TJ, Maskell D, Gay N, Bryant C. (2008). Elucidation of the MD-2/TLR4 interface required for signaling by lipid IVa. J Immunol, 181(2), 1245-1254. https://doi.org/10.4049/jimmunol.181.2.1245

Publication

Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
NlmUniqueID: 2985117R
Country: United States
Language: English
Volume: 181
Issue: 2
Pages: 1245-1254

Researcher Affiliations

Walsh, Catherine
  • Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
Gangloff, Monique
    Monie, Tom
      Smyth, Tomoko
        Wei, Bin
          McKinley, Trevelyan J
            Maskell, Duncan
              Gay, Nicholas
                Bryant, Clare

                  MeSH Terms

                  • Amino Acid Sequence
                  • Animals
                  • Cats
                  • Cell Line
                  • Glycolipids / immunology
                  • Glycolipids / metabolism
                  • Horses
                  • Humans
                  • Ligands
                  • Lipid A / analogs & derivatives
                  • Lipid A / immunology
                  • Lipid A / metabolism
                  • Lipopolysaccharide Receptors / immunology
                  • Lipopolysaccharide Receptors / metabolism
                  • Lymphocyte Antigen 96 / chemistry
                  • Lymphocyte Antigen 96 / genetics
                  • Lymphocyte Antigen 96 / immunology
                  • Lymphocyte Antigen 96 / metabolism
                  • Mice
                  • Molecular Sequence Data
                  • Point Mutation
                  • Protein Conformation
                  • Recombinant Fusion Proteins / immunology
                  • Recombinant Fusion Proteins / metabolism
                  • Sequence Alignment
                  • Signal Transduction
                  • Species Specificity
                  • Surface Properties
                  • Toll-Like Receptor 4 / chemistry
                  • Toll-Like Receptor 4 / genetics
                  • Toll-Like Receptor 4 / immunology
                  • Toll-Like Receptor 4 / metabolism

                  Grant Funding

                  • G0400007 / Medical Research Council
                  • G1000133 / Medical Research Council

                  Citations

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