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- Title
Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin.
- Authors
Mukherjee, Reshmi; Somovilla, Victor J.; Chiodo, Fabrizio; Bruijns, Sven; Pieters, Roland J.; Garssen, Johan; van Kooyk, Yvette; Kraneveld, Aletta D.; van Bergenhenegouwen, Jeroen
- Abstract
Human milk oligosaccharides (HMOs) and their most abundant component, 2′-Fucosyllactose (2′-FL), are known to be immunomodulatory. Previously, it was shown that HMOs and 2′-FL bind to the C-type lectin receptor DC-SIGN. Here we show, using a ligand-receptor competition assay, that a whole mixture of HMOs from pooled human milk (HMOS) and 2′-FL inhibit the binding of the carbohydrate-binding receptor DC-SIGN to its prototypical ligands, fucose and the oligosaccharide Lewis-B, (Leb) in a dose-dependent way. Interestingly, such inhibition by HMOS and 2′-FL was not detected for another C-type lectin, langerin, which is evolutionarily similar to DC-SIGN. The cell-ligand competition assay using DC-SIGN expressing cells confirmed that 2′-FL inhibits the binding of DC-SIGN to Leb. Molecular dynamic (MD) simulations show that 2′-FL exists in a preorganized bioactive conformation before binding to DC-SIGN and this conformation is retained after binding to DC-SIGN. Leb has more flexible conformations and utilizes two binding modes, which operate one at a time via its two fucoses to bind to DC-SIGN. Our hypothesis is that 2′-FL may have a reduced entropic penalty due to its preorganized state, compared to Leb, and it has a lower binding enthalpy, suggesting a better binding to DC-SIGN. Thus, due to the better binding to DC-SIGN, 2′-FL may replace Leb from its binding pocket in DC-SIGN. The MD simulations also showed that 2′-FL does not bind to langerin. Our studies confirm 2′-FL as a specific ligand for DC-SIGN and suggest that 2′-FL can replace other DC-SIGN ligands from its binding pocket during the ligand-receptor interactions in possible immunomodulatory processes.
- Subjects
LIGAND binding (Biochemistry); BREAST milk; BINDING site assay; OLIGOSACCHARIDES; HEALTH maintenance organizations; FUCOSE
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 23, p14745
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms232314745