Gangliosides are important components of the cell plasma membrane, especially in nervous tissue where they constitute about 10% of the total lipid. It has been found that gangliosides are involved in the recognition machinery of the cell, cell adhesion, cell-cell interactions and that they serve as receptors for glycopeptide hormone, neuropeptides, bacterial toxins and viruses. This research project is directed to study at the molecular level a major aspect of ganglioside function, namely, the role of gangliosides as cell surface receptors using well defined experimental systems. The molecular details and interactions of cholera toxin (CT) and the heat-labile enterotoxin of E. coli with their receptor ganglioside G(m1) will be studied using an experimental thermodynamic approach. The structural stability of these two proteins and their inter- and intra-subunit interactions will be studied in detail. Particularly, functionally relevant molecular interactions will be identified and their energetics measured using state-of-the-art ultra high sensitivity calorimetric techniques. The modulation of cooperative interactions within the toxin molecule by ganglioside G(M1) lead to: 1) the attachment of the toxin binding subunits to the cell surface; 2) the release of the toxic subunits from the binding subunits of the toxin molecules; and, 3) the subsequent penetration of the toxic subunits into the interior of the target membrane. These studies will provide a detailed quantitative description of the functional energetics of a specific ganglioside receptor.
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