What sugar next? Dimerization of sphingolipid glycosyltransferases

Abstract

One of the great riddles of glycobiology is the function of the glycosphingolipids. Their vital role is clear from the fact that the lack only of subsets of glycosphingolipids results in premature death (1). Hundreds of glycosphingolipids populate the surface of mammalian cells. These may serve a general function in membrane structure as their physical properties are different from those of the bulk glycerophospholipids (2). In contrast, the mammalian glycolipids are only a small subset of the millions of theoretical structures that can be formed from, for example, five monosaccharides. The large amount of structural information in their carbohydrate backbone makes them exquisitely suited for mediating specific interactions. Indeed, only a limited number of specific glycosphingolipids occur on a particular cell, and a defined set of enzymes is responsible for their ordered synthesis and degradation. Although some information is available about the transcriptional regulation of the various glycosyltransferases, most glycolipid synthesis occurs within a single cellular compartment (the late Golgi), and it is unclear how the relative amounts of the various glycosphingolipids are controlled. The paper by Giraudo et al. (3) reports the finding that two glycosyltransferases responsible for sequential steps in glycolipid assembly form a molecular complex. This result predicts channeling of substrates whereby the product of the first enzyme is preferentially used by the second and not by a competing transferase. Independent findings on glycosylation of lipids in the ER and proteins in the trans Golgi show that both homo- and heterodimerization are common themes in the organization of glycosylation events. Mammalian glycosphingolipids are synthesized by the stepwise addition of monosaccharides to ceramide (Fig. 1). Ceramide is synthesized in the ER, and the last glycosylation events occur in the late Golgi. An attractive possibility would …