Structural insight into the binding of human galectins to corneal keratan sulfate, its desulfated form and related saccharides

Miller, Michelle C.; Cai, Chao; Wichapong, Kanin; Bhaduri, Sayantan; Pohl, Nicola L. B.; Linhardt, Robert J.; Gabius, Hans-Joachim und Mayo, Kevin H. (2020): Structural insight into the binding of human galectins to corneal keratan sulfate, its desulfated form and related saccharides. In: Scientific Reports, Bd. 10, Nr. 1, 15708

Abstract

Glycosaminoglycan chains of keratan sulfate proteoglycans appear to be physiologically significant by pairing with tissue lectins. Here, we used NMR spectroscopy and molecular dynamics (MD) simulations to characterize interactions of corneal keratan sulfate (KS), its desulfated form, as well as di-, tetra-(N-acetyllactosamine and lacto-N-tetraose) and octasaccharides with adhesion/growth-regulatory galectins, in particular galectin-3 (Gal-3). The KS contact region involves the lectin canonical binding site, with estimated K-D values in the low mu M range and stoichiometry of similar to 8 to similar to 20 galectin molecules binding per polysaccharide chain. Compared to Gal-3, the affinity to Gal-7 is relatively low, signaling preferences among galectins. The importance of the sulfate groups was delineated by using desulfated analogs that exhibit relatively reduced affinity. Binding studies with two related di- and tetrasaccharides revealed a similar decrease that underscores affinity enhancement by repetitive arrangement of disaccharide units. MD-based binding energies of KS oligosaccharide-loaded galectins support experimental data on Gal-3 and -7, and extend the scope of KS binding to Gal-1 and -9N. Overall, our results provide strong incentive to further probe the relevance of molecular recognition of KS by galectins in terms of physiological processes in situ, e.g. maintaining integrity of mucosal barriers, intermolecular (lattice-like) gluing within the extracellular meshwork or synaptogenesis.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Tiermedizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2045-2322
• Sprache: Englisch