Interaction of Proteins with Lipid Rafts Through Glycolipid-Binding Domains:Biochemical Background and Potential Therapeutic Applications

Jacques      Fantini

Abstract

The wide biochemical diversity of glycolipids in membranes explains why these molecules are often selected by pathogens (viruses, bacteria, prions) as primary sites of interactions with the cell surface. Moreover, glycolipids concentrate into cholesterol/ glycolipid-rich microdomains where they can reach high local concentrations consistent with the multivalent attachment of pathogens on the cell surface. Finally, recent studies have shown that glycolipids could also modulate protein conformation. This chaperone activity of glycolipids has been associated with various pathogenic processes including HIV infection, prion propagation, and amyloid aggregation in Alzheimers and Creutzfeldt-Jakobs diseases. Despite the potential interest for drugs mimicking glycolipid structure and function, the physicochemical properties of authentic glycolipids suggested that it might be difficult to obtain synthetic glycolipid analogues able to neutralise those pathogens before they could reach the cell surface. Recent data obtained with mono-, di-, and trihexosylceramide (GalCer, LacCer and Gb3) have proven that this was absolutely not the case and that highly active inhibitors could be designed through slight modifications of glycolipid structure. Biochemical studies of glycolipid-protein interactions have highlighted the importance of CH- π stacking interactions between galactosyl head groups of the glycolipid and aromatic amino acids of the protein. The discovery of this unique mechanism of interaction may allow a rational strategy for the design and synthesis of glycolipid-based molecules as new anti-infectious and/or anti-amyloidogenesis compounds. This strategy, which takes into account the hierarchical organisation of glycolipids into discrete membrane microdomains as well as their association with cholesterol, is discussed in the present review.

Keywords: sphingolipids, GalCer, conformation, Creutzfeldt-Jakob diseases, glycolipid-binding domain

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