Glycan-to-Glycan Binding: Molecular Recognition through Polyvalent Interactions Mediates Specific Cell Adhesion.

Glycan-to-glycan binding was shown by biochemical and biophysical measurements to mediate xenogeneic self-recognition and adhesion in sponges, stage-specific cell compaction in mice embryos, and in vitro tumor cell adhesion in mammals. This intermolecular recognition process is accepted as the new paradigm accompanying high-affinity and low valent protein-to-protein and protein-to-glycan binding in cellular interactions. Glycan structures in sponges have novel species-specific sequences. Their common features are the large size >100 kD, polyvalency >100 repeats of the specific self-binding oligosaccharide, the presence of fucose, and sulfated and/or pyruvylated hexoses. These structural and functional properties, different from glycosaminoglycans, inspired their classification under the glyconectin name. The molecular mechanism underlying homophilic glyconectin-to-glyconectin binding relies on highly polyvalent, strong, and structure-specific interactions of small oligosaccharide motifs, possessing ultra-weak self-binding strength and affinity. Glyconectin localization at the glycocalyx outermost cell surface layer suggests their role in the initial recognition and adhesion event during the complex and multistep process. In mammals, Lex-to-Lex homophilic binding is structure-specific and has ultra-weak affinity. Cell adhesion is achieved through highly polyvalent interactions, enabled by clustering of small low valent structure in plasma membranes.

Functional Diversity of Neuronal Cell Adhesion and Recognition Molecule L1CAM through Proteolytic Cleavage.

The neuronal cell adhesion and recognition molecule L1 does not only 'keep cells together' by way of homophilic and heterophilic interactions, but can also promote cell motility when cleaved into fragments by several proteases. It has largely been thought that such fragments are signs of degradation. Now, it is clear that proteolysis contributes to the pronounced functional diversity of L1, which we have reviewed in this work. L1 fragments generated at the plasma membrane are released into the extracellular space, whereas other membrane-bound fragments are internalised and enter the nucleus, thus conveying extracellular signals to the cell interior. Post-translational modifications on L1 determine the sequence of cleavage by proteases and the subcellular localisation of the generated fragments. Inside the neuronal cells, L1 fragments interact with various binding partners to facilitate morphogenic events, as well as regenerative processes. The stimulation of L1 proteolysis via injection of L1 peptides or proteases active on L1 or L1 mimetics is a promising tool for therapy of injured nervous systems. The collective findings gathered over the years not only shed light on the great functional diversity of L1 and its fragments, but also provide novel mechanistic insights into the adhesion molecule proteolysis that is active in the developing and diseased nervous system.

Unmasking Fucosylation: from Cell Adhesion to Immune System Regulation and Diseases.

Fucosylation is a biological process broadly observed in vertebrates, invertebrates, plants, bacteria, and fungi. Fucose moieties on cell-surface glycans are increasingly recognized as critical to many cell-cell interaction and signaling processes. One of the characteristic roles of fucose is its regulation of selectin-dependent leukocyte adhesion that has been well studied over the last two decades. Recent studies of fucose in immune cell development and function regulation have significantly expanded the contemporary understanding of fucosylation. From cellular adhesion to immune regulation, herein we discuss the use of gene knockout studies, competitive inhibitors of fucose-containing glycan, and metabolic inhibitors of fucose biosynthesis to probe fucosylated glycan biosynthesis and signaling and its functional consequences. Promising clinical and preclinical applications in sickle cell disease, rheumatoid arthritis, tumor inhibition, metastasis prevention, antibody-dependent cell-mediated cytotoxicity, chemoresistance reversal, and in improving chemotherapy-related side effects and recovery are reviewed.