Molecular recognition of gangliosides and their potential for cancer immunotherapies

Abstract

Gangliosides are sialic-acid-containing glycosphingolipids expressed on all vertebrate cells. They are primarily positioned in the plasma membrane with the ceramide part anchored in the membrane and the glycan part exposed on the surface of the cell. These lipids have highly diverse structures, not the least with respect to their carbohydrate chains, with N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc) being the two most common sialic-acid residues in mammalian cells. Generally, human healthy tissue is deficient in NeuGc, but this molecule is expressed in tumors and in human fetal tissues, and was hence classified as an onco-fetal antigen. Gangliosides perform important functions through carbohydrate-specific interactions with proteins, for example, as receptors in cell-cell recognition, which can be exploited by viruses and other pathogens, and also by regulating signaling proteins, such as the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), through lateral interaction in the membrane. Through both mechanisms, tumor-associated gangliosides may affect malignant progression, which makes them attractive targets for cancer immunotherapies. In this review, we describe how proteins recognize gangliosides, focusing on the molecular recognition of gangliosides associated with cancer immunotherapy, and discuss the importance of these molecules in cancer research.

Keywords: biological membranes; cancer immunotherapy; cell signaling; gangliosides; glycosphingolipids; protein–carbohydrate interactions; sialic acid; tumor-associated antigens.

Figure 1

Schematic drawing of NeuAc GM3, a common ganglioside in vertebrate tissues. Carbohydrate symbols follow the nomenclature of the Consortium for Functional Glycomics (2); purple diamond – N-acetylneuraminic acid; yellow circle – D-galactose; blue circle – D-glucose.

Figure 2

Structures and biosynthetic pathways of gangliosides. The glycosyltransferases catalyzing the synthesis of gangliosides are shown in italics. Cer, ceramide; SA, sialic acid. Ganglioside nomenclature [according to Svennerholm (1)] is shown in boxes. Adapted from Ref. (5).

Figure 3

Example of ganglioside recognition [here: GT1b (analog) and its interaction with botulinum neurotoxin type A (BoNT/A)]. (A) Experimental electron density (Fo–Fc omit map) of the ganglioside head group. (B) Schematic drawing of the interactions between GT1b and BoNT/A. Hydrogen bonds are shown as dotted lines (red: intermolecular interactions; black: intramolecular carbohydrate–carbohydrate interactions). (C) Close-up view of the ligand-binding site. Please note the aromatic stacking interactions with Trp 1266 and Tyr 1117. Printed with permission from Ref. (40).

Figure 4

Glycosphingolipid interaction with cholesterol, an important constituent of lipid rafts. (A) GalCer, extended conformation. (B,C) GalCer, tilted conformation, induced by H-bonding interactions with cholesterol OH-group, shown in (C) [(A,B): space-filling representation, (C): stick representation]. Printed with permission from Ref. (56), in an extension of earlier work by Nyholm et al. (58).