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

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. 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.