Glycosphingolipid Functions

The combination of carbohydrate and lipid generates unusual molecules in which the two distinctive halves of the glycoconjugate influence the function of each other. Membrane glycolipids can act as primary receptors for carbohydrate binding proteins to mediate transmembrane signaling despite restriction to the outer bilayer leaflet. The extensive heterogeneity of the lipid moiety plays a significant, but still largely unknown, role in glycosphingolipid function. Potential interplay between glycolipids and their fatty acid isoforms, together with their preferential interaction with cholesterol, generates a complex mechanism for the regulation of their function in cellular physiology.The chemical identification of sphingosine/sphingomyelin by Thudichum (1884) marks the beginning of the enigma in terms of glycosphingolipid (GSLs) function. Their extensive compositional characterization, defines more than 300 species (Stults et al. 1989; Hakomori 2008). However, this large complement of chemically defined GSLs, containing on average 1–8 sugars, may significantly underrepresent the total GSL “glycome” because polyglycosyl ceramides, containing up to 60 sugar residues, have been described by Karlsson and colleagues (Miller-Podraza et al. 1993, 1997) but have not been followed up since their initial isolation.Despite early compositional definition, functional studies on GSLs lag behind other macromolecular biomolecules, (e.g., proteins, or even glycoproteins). Indeed, the revolution in molecular biology and structural biology seem to have largely by-passed GSLs. GSL crystal structures are extremely rare (Pascher and Sundell 1977), much rarer than membrane proteins, for example (Loll 2003). Three dimensional GSL structures have been attained within protein complex crystals, rather than as separate entities (Zajonc et al. 2003; Malinina et al. 2006; Wu et al. 2006), and these resolve structures largely incompatible with lamellar membrane presented GSLs.