Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin
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...
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2022-11-01
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author | Reshmi Mukherjee Victor J. Somovilla Fabrizio Chiodo Sven Bruijns Roland J. Pieters Johan Garssen Yvette van Kooyk Aletta D. Kraneveld Jeroen van Bergenhenegouwen |
author_facet | Reshmi Mukherjee Victor J. Somovilla Fabrizio Chiodo Sven Bruijns Roland J. Pieters Johan Garssen Yvette van Kooyk Aletta D. Kraneveld Jeroen van Bergenhenegouwen |
author_sort | Reshmi Mukherjee |
collection | DOAJ |
description | 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, (Le<sup>b</sup>) 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 Le<sup>b</sup>. 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. Le<sup>b</sup> 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 Le<sup>b</sup>, 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 Le<sup>b</sup> 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. |
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spelling | doaj.art-5e6c25f874b1419e8b6d767dcf6ce3852023-11-24T11:07:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231474510.3390/ijms232314745Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to LangerinReshmi Mukherjee0Victor J. Somovilla1Fabrizio Chiodo2Sven Bruijns3Roland J. Pieters4Johan Garssen5Yvette van Kooyk6Aletta D. Kraneveld7Jeroen van Bergenhenegouwen8Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The NetherlandsCenter for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramon 182, 20014 Donostia San Sebastián, SpainDepartment of Molecular Cell Biology and Immunology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Infection and Immunity Research Institute, De Boelelaan 1108, 1081 HZ Amsterdam, The NetherlandsDepartment of Molecular Cell Biology and Immunology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Infection and Immunity Research Institute, De Boelelaan 1108, 1081 HZ Amsterdam, The NetherlandsDivision of Chemical Biology and Drug Discovery, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The NetherlandsDivision of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The NetherlandsDepartment of Molecular Cell Biology and Immunology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Infection and Immunity Research Institute, De Boelelaan 1108, 1081 HZ Amsterdam, The NetherlandsDivision of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The NetherlandsDivision of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The NetherlandsHuman 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, (Le<sup>b</sup>) 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 Le<sup>b</sup>. 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. Le<sup>b</sup> 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 Le<sup>b</sup>, 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 Le<sup>b</sup> 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.https://www.mdpi.com/1422-0067/23/23/14745DC-SIGN2′-FLhuman milk oligosaccharideslangerinlewis B antigen |
spellingShingle | Reshmi Mukherjee Victor J. Somovilla Fabrizio Chiodo Sven Bruijns Roland J. Pieters Johan Garssen Yvette van Kooyk Aletta D. Kraneveld Jeroen van Bergenhenegouwen Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin International Journal of Molecular Sciences DC-SIGN 2′-FL human milk oligosaccharides langerin lewis B antigen |
title | Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin |
title_full | Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin |
title_fullStr | Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin |
title_full_unstemmed | Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin |
title_short | Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin |
title_sort | human milk oligosaccharide 2 fucosyllactose inhibits ligand binding to c type lectin dc sign but not to langerin |
topic | DC-SIGN 2′-FL human milk oligosaccharides langerin lewis B antigen |
url | https://www.mdpi.com/1422-0067/23/23/14745 |
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