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Publication Abstract from PubMed

Galectin-3 is crucial to many physiological and pathological processes. The generally accepted dogma is that galectins function extracellularly by binding specifically to beta(1-->4)-galactoside epitopes on cell surface glycoconjugates. Here, we used crystallography and NMR spectroscopy to demonstrate that negatively charged homogalacturonans (HG, linear polysaccharides of alpha(1-->4)-linked-D-galacturonate (GalA)) bind to the galectin-3 carbohydrate recognition domain. The HG carboxylates at the C6 positions in GalA rings mandate that this saccharide bind galectin-3 in an unconventional, "topsy-turvy" orientation that is flipped by about 180o relative to that of the canonical beta-galactoside lactose. In this binding mode, the reducing end GalA beta-anomer of HGs takes the position of the nonreducing end galactose residue in lactose. This novel orientation maintains interactions with the conserved tryptophan and seven of the most crucial lactose-binding residues, albeit with different H-bonding interactions. Nevertheless, the HG molecular orientation and new interactions have essentially the same thermodynamic binding parameters as lactose. Overall, our study provides structural details for a new type of galectin-sugar interaction that broadens glycospace for ligand binding to Gal-3 and suggests how the lectin may recognize other negatively charged polysaccharides like glycoaminoglycans (e.g. heparan sulfate) on the cell surface. This discovery impacts on our understanding of galectin-mediated biological function.

Topsy-turvy binding of negatively charged homogalacturonan oligosaccharides to galectin-3.,Zheng Y, Su J, Miller MC, Geng J, Xu X, Zhang T, Mayzel M, Zhou Y, Mayo KH, Tai G Glycobiology. 2020 Aug 17. pii: 5892985. doi: 10.1093/glycob/cwaa080. PMID:32909036^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.