title: Galectin-3 interactions with glycosphingolipids.
abstract: Galectins have essential roles in pathological states including cancer, inflammation, angiogenesis and microbial infections. Endogenous receptors include members of the lacto- and neolacto-series glycosphingolipids present on mammalian cells and contain the tetrasaccharides lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT) that form their core structural components and also ganglio-series glycosphingolipids. We present crystallographic structures of the carbohydrate recognition domain of human galectin-3, both wild type and a mutant (K176L) that influenced ligand affinity, in complex with LNT, LNnT and acetamido ganglioside a-GM3 (α2,3-sialyllactose). Key structural features revealed include galectin-3's demonstration of a binding mode towards gangliosides distinct from that to the lacto/neolacto-glycosphingolipids, with its capacity for recognising the core β-galactoside region being challenged when the core oligosaccharide epitope of ganglio-series glycosphingolipids (GM3) is embedded within particular higher-molecular-weight glycans. The lacto- and neolacto- glycosphingolipids revealed different orientations of their terminal galactose in the galectin-3-bound LNT and LNnT structures that has significant ramifications for the capacity of galectin-3 to interact with higher-order lacto/neolacto-series glycosphingolipids such as ABH blood group antigens and the HNK-1 antigen that is common on leukocytes. LNnT also presents an important model for poly-N-acetyllactosamine-containing glycans and provides insight into galectin-3's accommodation of extended oligosaccharides such as the poly-N-acetyllactosamine-modified N- and O-glycans that, via galectin-3 interaction, facilitate progression of lung and bladder cancers, respectively. These findings provide the first atomic detail of galectin-3's interactions with the core structures of mammalian glycosphingolipids, providing information important in understanding the capacity of galectin-3 to engage with receptors identified as facilitators of major disease.
authors: Institute for Glycomics, Griffith University Gold Coast Campus, Queensland 4222, Australia.
authors: Patrick M
authors: PM
authors: Collins
authors: Institute for Glycomics, Griffith University Gold Coast Campus, Queensland 4222, Australia.
authors: Khuchtumur
authors: K
authors: Bum-Erdene
authors: Institute for Glycomics, Griffith University Gold Coast Campus, Queensland 4222, Australia.
authors: Xing
authors: X
authors: Yu
authors: Institute for Glycomics, Griffith University Gold Coast Campus, Queensland 4222, Australia. Electronic address: h.blanchard@griffith.edu.au.
authors: Helen
authors: H
authors: Blanchard
mesh_terms: D037502:Galectin 3 / Q000737:chemistry* / Q000378:metabolism*; D006028:Glycosphingolipids / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D037502:Galectin 3; D006028:Glycosphingolipids; D009844:Oligosaccharides
keywords: X-ray structures; carbohydrate recognition; galectin; ganglioside; glycosphingolipid