Unraveling functional significance of natural variations of a human galectin by glycodendrimersomes with programmable glycan surface

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-05, Vol.112 (18), p.5585-5590
• Main Authors: Zhang, Shaodong, Moussodia, Ralph-Olivier, Vértesy, Sabine, André, Sabine, Klein, Michael L., Gabius, Hans-Joachim, Percec, Virgil
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Amino Acid Sequence; autoimmune diseases; Autoimmune Diseases - immunology; Binding sites; Carbohydrates; Cell Communication; Cell Membrane - metabolism; crosslinking; Galectins - chemistry; Humans; Lectins; Lectins - chemistry; Ligands; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Mutation; Physical Sciences; Polymorphism, Single Nucleotide; Polysaccharides - chemistry; Protein Binding; Protein Conformation; quantitative analysis; receptors; single nucleotide polymorphism; sugars
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1506220112

Surface-presented glycans (complex carbohydrates) are docking sites for adhesion/growth-regulatory galectins within cell–cell/matrix interactions. Alteration of the linker length in human galectin-8 and single-site mutation (F19Y) are used herein to illustrate the potential of glycodendrimersomes with programmable glycan displays as a model system to reveal the functional impact of natural sequence variations in trans recognition. Extension of the linker length slightly reduces lectin capacity as agglutinin and slows down aggregate formation at low ligand surface density. The mutant protein is considerably less active as agglutinin and less sensitive to low-level ligand presentation. The present results suggest that mimicking glycan complexity and microdomain occurrence on the glycodendrimersome surface can provide key insights into mechanisms to accomplish natural selectivity and specificity of lectins in structural and topological terms. Significance Lectins are endogenous sugar receptors involved in diverse physiological and disease-associated processes. The functional consequences of naturally occurring single-nucleotide polymorphism and alternative splicing in lectins has been explored using glycodendrimersomes, a versatile test system with programmable glycan (complex carbohydrates) display. Importantly, glycodendrimersomes facilitate quantitative determination of lectin-mediated cross-linking, a hallmark of their activity. Threshold and kinetic effects measured for a human galectin associated with autoimmune disease document the sensitivity of the test system and highlight its potential as a new and highly versatile supramolecular sensor for biomedical applications.