Molecular recognition across our cells' sugary coat
The traditional paradigm of biological interactions is that high affinity is essential for selectivity and activity. Yet, many essential functions of the sugary coat around our cells, the glycocalyx, are driven by transient but multivalent molecular interactions. Amongst them are cell-cell, cell-extracellular matrix and cell-pathogen recognition. The Richter Lab deploys physics and chemistry tools to resolve the molecular and physical mechanisms that underpin glycocalyx functions. This seminar will cover a few examples of our work.
One example pertains to ‘superselective’ recognition, that is, the ability to sharply discriminate cells by the density of a given receptor, as opposed to the conventional discrimination of cells by the presence vs. absence of that receptor. Cell surface glycans and their receptors are predestined for superselective recognition owing to the multivalent nature and low affinity of glycan-protein interactions. The level of glycan expression varies between cells and in pathology, but only rarely does a given glycan epitope disappear completely or appear de novo; instead, similar glycans are present on different cell types, but in different amounts. We have identified design rules for tuning superselective recognition, and harness these to mechanistically understand multivalent recognition at the cell surface, and to develop probes for the superselective targeting.
A second example explores the role of the polysaccharide hyaluronan (HA) in immune cell trafficking. To enter lymphatic capillaries, dendritic cells (DCs) navigate towards the junctions between endothelial cells where they dock with the lymphatic HA receptor LYVE-1 via their dense HA glycocalyx, itself anchored to the DC surface by the HA receptor CD44. With single molecule experiments, we have revealed that the mechanics of HA binding and detachment differ markedly between LYVE-1 (‘sliding’) and CD44 (‘sticking’), despite the two receptors having high structural similarity and comparable zero-force binding affinities. This striking example of the evolution of distinctive mechanical recognition may help DCs to retain their HA glycocalyx whilst migrating.
In a third example, we demonstrate using in vitro assays with molecularly defined glycocalyx models and cultured neurons, how multivalent glycan binding can promote cross-linking and phase separation in perineuronal nets, a specialised glycocalyx on neurons that controls neuronal plasticity.