Abstract
Galectin-3 (Gal-3) is recognized as a prognostic marker in several cancer types. Its involvement in tumor development and proliferation makes this lectin a promising target for early cancer diagnosis and anti-cancer therapies. Gal-3 recognizes poly-N-acetyllactosamine (LacNAc)-based carbohydrate motifs of glycoproteins and glycolipids with a high specificity for internal LacNAc epitopes. This study analyzes the mode and kinetics of binding of Gal-3 to a series of multivalent neo-glycoproteins presenting complex poly-LacNAc-based oligosaccharide ligands on a scaffold of bovine serum albumin. These neo-glycoproteins rank among the strongest Gal-3 ligands reported, with Kd reaching sub-nanomolar values as determined by surface plasmon resonance. Significant differences in the binding kinetics were observed within the ligand series, showing the tetrasaccharide capped with N,N′-diacetyllactosamine (LacdiNAc) as the strongest ligand of Gal-3 in this study. A molecular model of the Gal-3 carbohydrate recognition domain with docked oligosaccharide ligands is presented that shows the relations in the binding site at the molecular level. The neo-glycoproteins presented herein may be applied for selective recognition of Gal-3 both on the cell surface and in blood serum.
Highlights
Galectin-3 (Gal-3) is the only member of the chimeric subgroup of galectins [1] found in vertebrate animals
Significant differences in the binding kinetics were observed within the ligand series, showing the tetrasaccharide capped with N,N -diacetyllactosamine (LacdiNAc) as the strongest ligand of Gal-3 in this study
Though β-galactosides are generally recognized as Gal-3 ligands, we recently found that the terminal N,N -diacetyllactosamine (LacdiNAc; GalNAcβ1,4GlcNAc) epitope acts as a selective ligand of Gal-3 compared to galectin-1 [6,7]
Summary
Galectin-3 (Gal-3) is the only member of the chimeric subgroup of galectins [1] found in vertebrate animals It is overexpressed in many cancers, e.g., gastric, colorectal, breast tumors, hepatocellular and pancreatic carcinomas, melanomas or glioblastomas. The LacdiNAc disaccharide occurs in some Oand N-linked mammalian glycoproteins and has specialized functions [8,9]; it has been identified as a specific glyco-biomarker in several types of cancers [10,11,12]. Otherwise, it is overexpressed in parasites [13] and other organisms [14]. We evaluate eight oligosaccharide analogs of poly-LacNAc type by surface plasmon resonance studies, of which the LacdiNAc-LacNAc-decorated neo-glycoconjugate exhibits the highest binding affinity in sub-nanomolar range
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