Reviewing and identifying amino acids of human, murine, canine and equine TLR4 / MD-2 receptor complexes conferring endotoxic innate immunity activation by LPS/lipid A, or antagonistic effects by Eritoran, in contrast to species-dependent modulation by lipid IVa.
Abstract: There is literature evidence gathered throughout the last two decades reflecting unexpected species differences concerning the immune response to lipid IVa which provides the opportunity to gain more detailed insight by the molecular modeling approach described in this study. Lipid IVa is a tetra-acylated precursor of lipid A in the biosynthesis of lipopolysaccharide (LPS) in Gram-negative bacteria. Lipid A of the prototypic E. coli-type is a hexa-acylated structure that acts as an agonist in all tested mammalian species by innate immunorecognition via the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) receptor complex. In contrast, lipid IVa is proinflammatory in mouse cells (agonism) but it remains inactive to human macrophages and even antagonizes the action of potent agonists like E. coli-type lipid A. This particular ambivalent activity profile of lipid IVa has been confirmed in other mammalian species: in equine cells Lipid IVa also acts in a weak agonistic manner, whereas being inactive and antagonizing the lipid A-induced activation of canine TLR4/MD-2. Intriguingly, the respective TLR4 amino acid sequences of the latter species are more identical to the human (67%, 68%) than to the murine (62%, 58%) ortholog. In order to address the unpaired activity-sequence dualism for human, murine, canine and equine species regarding the activity of lipid IVa as compared to LPS and lipid A and, we review the literature and computationally pinpoint the differential biological effects of lipid IVa versus LPS and lipid A to specific amino acid residues. In contrast to lipid IVa the structurally related synthetic compound Eritoran (E5564) acts consistently in an antagonistic manner in these mammalian species and serves as a reference ligand for molecular modeling in this study. The combined evaluation of data sets provided by prior studies and in silico homology mapping of differential residues of TLR4/MD-2 complexes lends detailed insight into the driving forces of the characteristic binding modes of the lipid A domain in LPS and the precursor structure lipid IVa to the receptor complex in individual mammalian species.
Publication Date: 2013-04-05 PubMed ID: 24688705PubMed Central: PMC3962135DOI: 10.5936/csbj.201302012Google Scholar: Lookup
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Summary
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The research investigates the role of lipid A and lipid IVa in activating the immune response in different animal species, using molecular modeling to identify key amino acid residues. This study also considers the different effects of the lipid A in E. coli-type and the impact of Eritoran, a synthetic compound related to lipid IVa.
Understanding Lipid A and Lipid IVa
- Lipid A and lipid IVa are parts of lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria. They play a crucial role in the immune response, affecting the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 (MD-2) receptor complex.
- Evidence from various studies has shown that the immune response against lipid IVa, specifically, varies between species. This variance is intriguing because it provides a unique opportunity to study the molecular interactions driving these differences.
The Role and Impact of Lipids in Different Species
- The research discusses how lipid IVa and lipid A affect different mammals, including humans, mice, dogs, and horses. It reveals that while lipid A triggers an immune response in all tested species, the effect of lipid IVa is not consistent.
- Interestingly, lipid IVa stimulates an immune response in mouse cells (acting as an agonist or “activator”), but remains inactive in human cells. In some cases, it even counteracts the effects of lipid A, behaving as an antagonist.
- This ambivalent activity of lipid IVa has been observed in other species as well. In equine cells, lipid IVa has a weak agonistic impact, while it is inactive and counteracts lipid A-induced activation in canine TLR4/MD-2.
- It’s worth noting that the human and canine TLR4 amino acid sequences are more similar to each other than they are to the murine sequence, which may contribute to their similar response to lipid IVa.
Theoretical Modelling Approach
- The research delves deep into the molecular characteristics of these lipids and how they interact with the TLR4/MD-2 complex to produce the observed effects. Using in silico homology mapping and computational modelling, the researchers are able to identify specific amino acid residues that could account for the different immune responses in various species.
- The research also compares the effects of the synthetic compound Eritoran with those of lipid IVa. Unlike lipid IVa, Eritoran consistently acts as an antagonist in all tested species. Consequently, Eritoran served as a comparative reference for molecular modelling.
Insights from the Research
- This research points to the importance of lipid IVa and lipid A in the immune response, especially in relation to the TLR4/MD-2 receptor complex. Understanding the complexity of interaction between lipids and this complex can potentially shed light on strategies for therapeutic interventions in immune-related conditions.
- The study also identifies specific amino acid residues that play critical roles in lipid-IVa-TLR4/MD-2 interactions, revealing their differences among species. These differences could be significant in studying and developing species-specific drugs or treatments.
- Furthermore, the research provides a clear example of how computational modelling can be effectively used in the investigation of complex biological phenomena, facilitating the understanding of intricate molecular interactions that are not easily observed through traditional experimental methods.
Cite This Article
APA
Scior T, Alexander C, Zaehringer U.
(2013).
Reviewing and identifying amino acids of human, murine, canine and equine TLR4 / MD-2 receptor complexes conferring endotoxic innate immunity activation by LPS/lipid A, or antagonistic effects by Eritoran, in contrast to species-dependent modulation by lipid IVa.
Comput Struct Biotechnol J, 5, e201302012.
https://doi.org/10.5936/csbj.201302012 Publication
Researcher Affiliations
- Departamento de Farmacia, Benemerita Universidad Autonoma de Puebla, C.P. 72570 Puebla, Pue., Mexico.
- Division of Immunochemistry, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
- Division of Immunochemistry, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
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