| Institution: | 1. Disease Glycomics Team, Global Research Cluster, RIKEN, Saitama 351-0198, Japan;2. Central Research Laboratories, Seikagaku Corporation, Tokyo 207-0021, Japan;3. Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu 501-1193, Japan;4. Structural Glycobiology Team, Global Research Cluster, RIKEN, Saitama 351-0198, Japan;5. Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan;6. University of Veterinary Medicine Hannover, Research Center for Emerging Infections and Zoonoses (RIZ), Infection Immunology, Hannover 30559, Germany;g. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam 14424, Germany;h. Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin 14195, Germany;i. Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan;j. Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo 160-8582, Japan;k. The Respiratory Care Clinic, Nippon Medical School, Tokyo 102-0074, Japan;l. Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan;m. Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan |
| Abstract: | BackgroundLangerin, a C-type lectin receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti-inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application.MethodsWe performed binding analysis between purified long and short forms of langerin and a series of KS disaccharide components. We also chemically synthesized oligomeric derivatives of L4 to develop a new high-affinity ligand of langerin.ResultsWe show that the binding critically requires the 6-sulfation of Gal and that the long form of langerin displays higher affinity than the short form. The synthesized trimeric (also designated as triangle or Tri) and polymeric (pendant) L4 derivatives displayed over 1000-fold higher affinity toward langerin than monomeric L4. The pendant L4, but not the L4 monomer, was found to effectively transduce langerin signaling in a model cell system.ConclusionsL4 is a specific ligand for langerin. Oligomerization of L4 unit increased the affinity toward langerin.General significanceThese results suggest that oligomeric L4 derivatives will be useful for clarifying the langerin functions and for the development of new glycan-based anti-inflammatory drugs. |
