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Ippel, Hans; Miller, Michelle C.; Vértesy, Sabine; Zheng, Yi; Javier Cañada, F.; Suylen, Dennis; Umemoto, Kimiko; Romano, Cecilia; Hackeng, Tilman; Tai, Guihua; Leffler, Hakon; Kopitz, Jürgen; André, Sabine; Kübler, Dieter; Jiménez-Barbero, Jesús; Oscarson, Stefan; Gabius, Hans-Joachim and Mayo, Kevin H. (2016): Intra- and intermolecular interactions of human galectin-3: assessment by full-assignment-based NMR. In: Glycobiology, Vol. 26, No. 8: pp. 888-903

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Galectin-3 is an adhesion/growth-regulatory protein with a modular design comprising an N-terminal tail ( NT, residues 1-111) and the conserved carbohydrate recognition domain ( CRD, residues 112-250). The chimera-type galectin interacts with both glycan and peptide motifs. Complete C-13/N-15-assignment of the human protein makes NMR-based analysis of its structure beyond the CRD possible. Using two synthetic NT polypeptides covering residues 1-50 and 51-107, evidence for transient secondary structure was found with helical conformation from residues 5 to 15 as well as proline-mediated, multi-turn structure from residues 18 to 32 and around PGAYP repeats. Intramolecular interactions occur between the CRD F-face ( the 5-stranded beta-sheet behind the canonical carbohydrate-binding 6-stranded beta-sheet of the S-face) and NT in full-length galectin-3, with the sequence P(23)GAW(26)... P(37)GASYPGAY(45) defining the primary binding epitope within the NT. Work with designed peptides indicates that the PGAX motif is crucial for self-interactions between NT/CRD. Phosphorylation at position Ser6 ( and Ser12) ( a physiological modification) and the influence of ligand binding have minimal effect on this interaction. Finally, galectin-3 molecules can interact weakly with each other via the F-faces of their CRDs, an interaction that appears to be assisted by their NTs. Overall, our results add insight to defining binding sites on galectin-3 beyond the canonical contact area for beta-galactosides.

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