The search for glycan function: Fucosylation of the TGF-β1 receptor is required for receptor activation

摘要

Interest in glycobiology was for many years restricted by a lack of information on the functions of glycans. The diversity of linkages and branching patterns present in glycans confers on them the ability to carry a great deal of information in very compact structures. Glycans conjugated to proteins by β-linkage of N-acetylglucosamine (GlcNAc) to the amido group of Asn (N-glycans) and by α1-O-glycosyl linkage of N-acetylgalac-tosamine (GalNAc), mannose (Man), and fucose (Fuc) to Ser and Thr (O-glycans) are primarily membrane-bound or extracellular. These and other considerations suggested that N- and O-glycans play essential roles in the interactions of cells with their cellular and fluid environments. Over the past 10 years, studies on mice and humans with mutations that result in defective protein N- and O-glycosylation have proved this hypothesis to be correct. To date, at least 30 mutant mice and 23 human congenital diseases have been described with null mutations in genes involved in protein N- and O-glycosylation. In a relatively small number of these mutant mice and humans it has been possible to construct a reasonably accurate scenario of the molecular mechanisms involved in the production of the phenotype because it has been possible to identify a specific protein target of the mutant enzyme and study the role of the glycan in the function of that target protein. The article by Wang et al. (13) in this issue of PNAS is an important example of such a situation. However, for most of the mutant mice and humans, the mutant enzyme alters the glycosylation of a large number of different glycoproteins, and it is not possible to deduce the precise molecular mechanisms responsible for the phenotype.