The structural basis for the susceptibility of gangliosides to enzymatic degradation

The conformational properties of GM2, GalNac beta-4(Neu5Ac alpha-3) Gal beta-4Glc beta-1Cer have been compared to those of 6'-GM2, in which the linkage between the GalNAc and Gal was altered from GalNAc beta-4Gal beta- to GalNac beta-6Gal beta-, and to those of GD1a, Neu5Ac alpha-3Gal beta-3GalNAc beta-4(Neu5Ac alpha-3)Gal beta-4Glc beta-1Cer, and GalNAc-GD1a. Our results revealed that unlike the compact and rigid oligosaccharide head group found in GM2, where the Neu5Ac and the GalNAc residues interact, the sugar chain of 6'-GM2 is in an open spatial arrangement, with the Neu5Ac no longer interacting with GalNAc, freely accessible to external interactions. The structure of GD1a can be regarded as that of GM2 with an extension of the terminal Neu5Ac alpha-3Gal beta-disaccharide. The inner portion of GD1a is that of GM2 comprising the very rigid GalNAc-[Neu5Ac-]Gal trisaccharide. The terminal Neu5Ac-Gal linkage is flexible and fluctuates between two limiting conformations. In GalNAc-GDla the outer sialic acid gains conformational rigidity due to the presence of the outer GalNAc in position 4 of galactose. This ganglioside has two 'core' GalNAc-[Neu5Ac-]Gal trisaccharide linked in tandem.