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Recognition of lipid A variants by the TLR4-MD-2 receptor complex.

Maeshima N, Fernandez RC - Front Cell Infect Microbiol (2013)

Bottom Line: LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokines that initiate and shape the adaptive immune response.Thus, it has been hypothesized that expression of lipid A variants is one mechanism by which pathogens modulate or evade the host immune response.Additionally, several key differences in the amino acid sequences of human and mouse TLR4-MD-2 receptors have been shown to alter the ability to recognize these variations in lipid A, suggesting a host-specific effect on the immune response to these pathogens.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.

ABSTRACT
Lipopolysaccharide (LPS) is a component of the outer membrane of almost all Gram-negative bacteria and consists of lipid A, core sugars, and O-antigen. LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokines that initiate and shape the adaptive immune response. Most of what is known about how LPS is recognized by the TLR4-MD-2 receptor complex on animal cells has been studied using Escherichia coli lipid A, which is a strong agonist of TLR4 signaling. Recent work from several groups, including our own, has shown that several important pathogenic bacteria can modify their LPS or lipid A molecules in ways that significantly alter TLR4 signaling to NFκB. Thus, it has been hypothesized that expression of lipid A variants is one mechanism by which pathogens modulate or evade the host immune response. Additionally, several key differences in the amino acid sequences of human and mouse TLR4-MD-2 receptors have been shown to alter the ability to recognize these variations in lipid A, suggesting a host-specific effect on the immune response to these pathogens. In this review, we provide an overview of lipid A variants from several human pathogens, how the basic structure of lipid A is recognized by mouse and human TLR4-MD-2 receptor complexes, as well as how alteration of this pattern affects its recognition by TLR4 and impacts the downstream immune response.

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Simplified diagram of TLR4-MD-2 receptor complex dimerization upon ligation of hexa-acyl lipid A. The amphipathic lipid A molecule consists of negatively-charged (indicated by a circle with a “−” sign in it) phosphate groups and hydrophobic fatty acyl chains. The fatty acyl chains sit inside the “binding pocket” structure of the MD-2 co-receptor protein, which is lined with hydrophobic amino acid residues, while the phosphate groups are engaged by charged amino acids in MD-2 at the mouth of the pocket. In the next part of the figure, we show lipid A inside the MD-2 pocket and also in contact with TLR4, with which it forms a 1:1 complex. Upon lipid A binding, this TLR4-MD-2 complex dimerizes with a second complex. From this position, lipid A engages the TLR4 molecule in the second complex (TLR4*) at two main interfaces: the first is mediated by interaction of the 6th acyl chain of lipid A (which is shown sticking out of the pocket) with uncharged amino acids (cloud labeled “neutral”) on TLR4*, the second is mediated by interaction of the negatively-charged 1-phosphate (1-PO4) on lipid A with positively-charged amino acid residues (cloud labeled “+”) on TLR4*.
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Figure 4: Simplified diagram of TLR4-MD-2 receptor complex dimerization upon ligation of hexa-acyl lipid A. The amphipathic lipid A molecule consists of negatively-charged (indicated by a circle with a “−” sign in it) phosphate groups and hydrophobic fatty acyl chains. The fatty acyl chains sit inside the “binding pocket” structure of the MD-2 co-receptor protein, which is lined with hydrophobic amino acid residues, while the phosphate groups are engaged by charged amino acids in MD-2 at the mouth of the pocket. In the next part of the figure, we show lipid A inside the MD-2 pocket and also in contact with TLR4, with which it forms a 1:1 complex. Upon lipid A binding, this TLR4-MD-2 complex dimerizes with a second complex. From this position, lipid A engages the TLR4 molecule in the second complex (TLR4*) at two main interfaces: the first is mediated by interaction of the 6th acyl chain of lipid A (which is shown sticking out of the pocket) with uncharged amino acids (cloud labeled “neutral”) on TLR4*, the second is mediated by interaction of the negatively-charged 1-phosphate (1-PO4) on lipid A with positively-charged amino acid residues (cloud labeled “+”) on TLR4*.

Mentions: In the following section, the basic mechanism underlying E. coli hexa-acyl lipid A recognition by the host (human) TLR4-MD-2 receptor complex will be discussed. We have summarized this in simplified cartoon form in Figure 4. Briefly, the lipid A portion of LPS sits partially inside the co-receptor protein MD-2. Both lipid A and MD-2 interact directly with TLR4. Upon ligand (lipid A) binding, this complex of TLR4 and MD-2 dimerizes with a second TLR4-MD-2 complex, which facilitates signaling to downstream effectors. Although many amino acid residues in both TLR4 and MD-2 have been identified as contributing to this interaction, we have focused on two key interfaces where lipid A interacts with the second TLR4 molecule in the dimerized complex in order to discuss the potential significance of modification of the regions of lipid A found to interact at these interfaces.


Recognition of lipid A variants by the TLR4-MD-2 receptor complex.

Maeshima N, Fernandez RC - Front Cell Infect Microbiol (2013)

Simplified diagram of TLR4-MD-2 receptor complex dimerization upon ligation of hexa-acyl lipid A. The amphipathic lipid A molecule consists of negatively-charged (indicated by a circle with a “−” sign in it) phosphate groups and hydrophobic fatty acyl chains. The fatty acyl chains sit inside the “binding pocket” structure of the MD-2 co-receptor protein, which is lined with hydrophobic amino acid residues, while the phosphate groups are engaged by charged amino acids in MD-2 at the mouth of the pocket. In the next part of the figure, we show lipid A inside the MD-2 pocket and also in contact with TLR4, with which it forms a 1:1 complex. Upon lipid A binding, this TLR4-MD-2 complex dimerizes with a second complex. From this position, lipid A engages the TLR4 molecule in the second complex (TLR4*) at two main interfaces: the first is mediated by interaction of the 6th acyl chain of lipid A (which is shown sticking out of the pocket) with uncharged amino acids (cloud labeled “neutral”) on TLR4*, the second is mediated by interaction of the negatively-charged 1-phosphate (1-PO4) on lipid A with positively-charged amino acid residues (cloud labeled “+”) on TLR4*.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569842&req=5

Figure 4: Simplified diagram of TLR4-MD-2 receptor complex dimerization upon ligation of hexa-acyl lipid A. The amphipathic lipid A molecule consists of negatively-charged (indicated by a circle with a “−” sign in it) phosphate groups and hydrophobic fatty acyl chains. The fatty acyl chains sit inside the “binding pocket” structure of the MD-2 co-receptor protein, which is lined with hydrophobic amino acid residues, while the phosphate groups are engaged by charged amino acids in MD-2 at the mouth of the pocket. In the next part of the figure, we show lipid A inside the MD-2 pocket and also in contact with TLR4, with which it forms a 1:1 complex. Upon lipid A binding, this TLR4-MD-2 complex dimerizes with a second complex. From this position, lipid A engages the TLR4 molecule in the second complex (TLR4*) at two main interfaces: the first is mediated by interaction of the 6th acyl chain of lipid A (which is shown sticking out of the pocket) with uncharged amino acids (cloud labeled “neutral”) on TLR4*, the second is mediated by interaction of the negatively-charged 1-phosphate (1-PO4) on lipid A with positively-charged amino acid residues (cloud labeled “+”) on TLR4*.
Mentions: In the following section, the basic mechanism underlying E. coli hexa-acyl lipid A recognition by the host (human) TLR4-MD-2 receptor complex will be discussed. We have summarized this in simplified cartoon form in Figure 4. Briefly, the lipid A portion of LPS sits partially inside the co-receptor protein MD-2. Both lipid A and MD-2 interact directly with TLR4. Upon ligand (lipid A) binding, this complex of TLR4 and MD-2 dimerizes with a second TLR4-MD-2 complex, which facilitates signaling to downstream effectors. Although many amino acid residues in both TLR4 and MD-2 have been identified as contributing to this interaction, we have focused on two key interfaces where lipid A interacts with the second TLR4 molecule in the dimerized complex in order to discuss the potential significance of modification of the regions of lipid A found to interact at these interfaces.

Bottom Line: LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokines that initiate and shape the adaptive immune response.Thus, it has been hypothesized that expression of lipid A variants is one mechanism by which pathogens modulate or evade the host immune response.Additionally, several key differences in the amino acid sequences of human and mouse TLR4-MD-2 receptors have been shown to alter the ability to recognize these variations in lipid A, suggesting a host-specific effect on the immune response to these pathogens.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.

ABSTRACT
Lipopolysaccharide (LPS) is a component of the outer membrane of almost all Gram-negative bacteria and consists of lipid A, core sugars, and O-antigen. LPS is recognized by Toll-like receptor 4 (TLR4) and MD-2 on host innate immune cells and can signal to activate the transcription factor NFκB, leading to the production of pro-inflammatory cytokines that initiate and shape the adaptive immune response. Most of what is known about how LPS is recognized by the TLR4-MD-2 receptor complex on animal cells has been studied using Escherichia coli lipid A, which is a strong agonist of TLR4 signaling. Recent work from several groups, including our own, has shown that several important pathogenic bacteria can modify their LPS or lipid A molecules in ways that significantly alter TLR4 signaling to NFκB. Thus, it has been hypothesized that expression of lipid A variants is one mechanism by which pathogens modulate or evade the host immune response. Additionally, several key differences in the amino acid sequences of human and mouse TLR4-MD-2 receptors have been shown to alter the ability to recognize these variations in lipid A, suggesting a host-specific effect on the immune response to these pathogens. In this review, we provide an overview of lipid A variants from several human pathogens, how the basic structure of lipid A is recognized by mouse and human TLR4-MD-2 receptor complexes, as well as how alteration of this pattern affects its recognition by TLR4 and impacts the downstream immune response.

Show MeSH
Related in: MedlinePlus