Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico

Autor: Mobarak, Edouard, Håversen, Liliana, Manna, Moutusi, Rutberg, Mikael, Levin, Malin, Perkins, Rosie, Rog, Tomasz, Vattulainen, Ilpo, Borén, Jan
Přispěvatelé: Department of Physics, Tampere University, Physics, Research group: Biological Physics and Soft Matter
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Lipopolysaccharides
Male
Protein Conformation
alpha-Helical
STRUCTURAL BASIS
MOLECULAR-DYNAMICS SIMULATIONS
Primary Cell Culture
Lymphocyte Antigen 96
Gene Expression
SIGNAL-TRANSDUCTION
lcsh:Medicine
Molecular Dynamics Simulation
Glucosylceramides
ATOMISTIC SIMULATIONS
114 Physical sciences
Article
Mice
Animals
Humans
Protein Interaction Domains and Motifs
lcsh:Science
ATOM FORCE-FIELD
TOLL-LIKE RECEPTORS
Binding Sites
Macrophage Colony-Stimulating Factor
Macrophages
Myelin and Lymphocyte-Associated Proteolipid Proteins
Cell Membrane
lcsh:R
Cell Differentiation
Hematopoietic Stem Cells
Mice
Inbred C57BL
Toll-Like Receptor 4
SWISS-MODEL
LIPID RAFTS
HEK293 Cells
TLR4-MD-2 COMPLEX
Glucosyltransferases
HUMAN ATHEROSCLEROTIC PLAQUE
1182 Biochemistry
cell and molecular biology
Protein Conformation
beta-Strand
lipids (amino acids
peptides
and proteins)
lcsh:Q
Protein Binding
Signal Transduction
Zdroj: Scientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
Mobarak, E, Håversen, L, Manna, M, Rutberg, M, Levin, M, Perkins, R, Rog, T, Vattulainen, I & Borén, J 2018, ' Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico ', Scientific Reports, vol. 8, 13600 . https://doi.org/10.1038/s41598-018-31926-0
Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/s41598-018-31926-0
Popis: Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS), which drives the production of proinflammatory cytokines. Earlier studies have indicated that cholesterol- and glycosphingolipid-rich subregions of the plasma membrane (lipid domains) are important for TLR4-mediated signaling. We report that inhibition of glucosylceramide (GluCer) synthase, which resulted in decreased concentrations of the glycosphingolipid GluCer in lipid domains, reduced the LPS-induced inflammatory response in both mouse and human macrophages. Atomistic molecular dynamics simulations of the TLR4 dimer complex (with and without LPS in its MD-2 binding pockets) in membranes (in the presence and absence of GluCer) showed that: (1) LPS induced a tilted orientation of TLR4 and increased dimer integrity; (2) GluCer did not affect the integrity of the LPS/TLR4 dimer but reduced the LPS-induced tilt; and (3) GluCer increased electrostatic interactions between the membrane and the TLR4 extracellular domain, which could potentially modulate the tilt. We also showed that GCS inhibition reduced the interaction between TLR4 and the intracellular adaptor protein Mal. We conclude that the GluCer-induced effects on LPS/TLR4 orientation may influence the signaling capabilities of the LPS/TLR4 complex by affecting its interaction with downstream signaling proteins. publishedVersion
Databáze: OpenAIRE
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