The structural basis for the susceptibility of gangliosides to enzymatic degradation

The conformational properties of GM2, GalNacbeta-4(Neu5Acalpha-3) Galbeta-4Glcbeta-1Cer have been compared to those of 6'-GM2, in which the linkage between the GalNAc and Gal was altered from GalNacbeta-4Galbeta- to GalNacbeta-6Galbeta-, and to those of GD1a, Neu5Acalpha-3Galbeta-3GalNAcbeta-4(Neu5Acalpha-3 )Galbeta-4Glcbeta-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 Neu5Acalpha-3Galbeta-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-GD1a 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.