Hetero-Multivalent Binding of Lectin to Glycans on Cell Membranes

Abstract

Most lectins bind to glycans via multivalent interactions to enhance the overall binding avidity. Because of the fluidic nature of cell membranes, glycans attached to lipids (glycolipids) or proteins (glycoproteins) on cell membranes can freely diffuse on the two dimensional surface, eventually leading to multivalent interactions with lectins. We recently discovered that such two-dimensional motion can assist the low-affinity glycolipid ligands, whose dissociation constants are in the millimolar range, to participate in the lectin binding events even though the concentration of the lectin is in the nanomolar range. Interestingly, through a newly discovered “ligand-exchange mechanism”, a lectin can be stabilized entirely by low-affinity ligands. Our new discovery offers a potential answer for a long-standing question in glycobiology, why some lectins could significantly bind to the cells when their primary glycan ligands have low abundance. Additionally, the participation of low-affinity glycolipid ligand could significantly alter the lectin binding behaviors (i.e. avidities, capacities, and kinetics). Here, we have used analytical assays and computer simulations to explore the influence of cell membranes on lectin binding behaviors. We have surveyed a number of conditions and identified the critical variables influencing lectin-glycolipid recognitions. Our findings suggest that cells probably use the membrane fluidity and secondary ligands to control the lectin binding, in order to regulate the downstream biochemical reactions. The concept of hetero-multivalent binding provides the molecular basis of a popular hypothesis in glycobiology: lectins are pattern recognition receptors, which recognize glycan epitopes based on their number, density, and spatial distribution, in addition to their molecular structures.