STRUCTURAL BASIS OF GANGLIOSIDE RECOGNITION

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

Gangliosides contain complex carbohydrates attached to lipids and play essential roles in cell signaling. The GM2 activator protein (GM2-AP) is an essential cofactor in mammalian lysosomes for conversion of GM2 to GM3 by beta-hexosaminidase A. Deficiency of GM2-AP results in type AB Tay Sachs disease, a fatal genetic disorder. To investigate the specific activating function of GM2-AP and its affinity for glycolipid acyl chains, x-ray structures of both human and mouse GM2-AP are being determined as well as the structure of the mouse GM2 ligand complex. The crystal structure of the selenomethionine mutant of the GM2-AP has been solved at 2.4 A by multiwavelength anomalous diffraction. The plan is to refine the human GM2-AP structure and to solve the apo-mouse GM2-AP and its complex with GM2 at 2.5 A by molecular replacement. The resulting molecular models will be analyzed for conformational differences. Additional structural studies of human Tay Sachs mutants (R138P and C107R) will further unravel the functional role of specific protein side chains in the disease. Finally, to investigate how gangliosides are recognized in other proteins, new structural studies are proposed on sulfatide activator protein (SAP-B), a small dimeric protein known to stimulate the hydrolysis of GM1 by beta-galactosidase.