Dystroglycan and Cell Adhesion
	Dystroglycan was originally identified in skeletal muscle as a component of the dystrophin-glycoprotein complex. It is composed of alpha- and beta-subunits which are encoded by a single gene, and cleaved into two proteins by posttranslational processing. Based on recent amino-terminal sequencing of beta-dystroglycan, it was proposed that the serine residue at position 654 of the precursor protein of dystroglycan is the cleavage site. alpha-Dystroglycan is an extracellular peripheral membrane glycoprotein anchored to the cell membrane by binding to a transmembrane glycoprotein, beta-dystroglycan. In skeletal muscle, alpha-dystroglycan binds the extracellular matrix components laminin-1 and -2 in a Ca2+-dependent manner. On the cytoplasmic side of the sarcolemma, beta-dystroglycan is anchored to the cytoskeletal proteins dystrophin and its homologues, which are associated with the F-actin. Thus, dystroglycan spans the sarcolemma providing a connection between the extracellular matrix and the cytoskeleton. Therefore, the connection between the extracellular matrix and the cytoskeleton provided by dystroglycan serve to stabilize the sarcolemma during contraction-induced stress. Dystrophin deficiency causes a drastic reduction of the dystroglycan complex in the sarcolemma and, thus, loss of linkage between the subsarcolemmal cytoskeleton and the extracellular matrix, eventually leading to muscle cell death in Duchenne muscular dystrophy. Skeletal muscle dystroglycan is also localized to the neuromuscular junction where alpha-dystroglycan binds to agrin, which is a component of the extracellular matrix proteins that induce the aggregation of acetylcholine receptors of the postsynaptic membrane. However, it is unclear whether dystroglycan is directly transducing the signal from agrin that initiates the clustering of acetylcholine receptors. Dystroglycan's exact role in the development of the neuromuscular junction remains unclear.
	Figure 1 Schematic model of the dystrophin-glycoprotein complex as a transsarcolemmal linker between the subsarcolemmal cytoskeleton and extracellular matrix.
	Dystroglycan is also expressed in a broad array of non-muscle tissues. Dystroglycan's function in these non-muscle tissue is largely unknown, although in some cases its function has been inferred from its subcellular localization. For example, in the peripheral nervous system, it is expressed in the Schwann cell membrane, and the Schwann cell alpha dystroglycan also binds laminin. Recent studies suggest roles for the dtstroglycan-laminin interaction in the peripheral myelinogenesis. Further, in the brain, this interaction is suggested to probably play an important role in the integrity of the glial-vascular interface. alpha-Dystroglycan is heavily glycosylated. Whereas the deduced amino-acid sequence predicts a ~74 kDa core peptide, alpha-dystroglycan is identified as an apparent molecular mass of 156 kDa in skeletal muscle, 120 kDa in brain and peripheral nerve, and 190 kDa in postsynaptic membrane of Torpedo electric organ. The differences in the molecular masses of alpha-dystroglycans obtained from different tissues seem to be due, not to differences in the primary structure, but to tissue-specific differential glycosylation of the core protein. Although the nature of the carbohydrate moiety of alpha-dystroglycan has not been fully clarified yet, chemical modification of sugar moieties and/or sialidase digestion resulted in the loss of laminin-binding, suggesting that the sialic acid residues of alpha-dystroglycan, which are probably attached to O-linked oligosaccharides, are essential for this activity. A recent study analyzed the structures of sialylated O-linked oligosaccharides of bovine peripheral nerve alpha-dystroglycan, and demonstrated that a novel O-linked mannose type oligosaccharide, Sia alpha2-3Gal beta1-4GlcNAc beta1-2Man, is the major component. The results of a binding-inhibition study suggest that this unique oligosaccharide contributes to the laminin-binding activity of alpha-dystroglycan. The study of targeted disruption of dystroglycan gene in the mouse indicated that dystroglycan may be required for the assembly of the extracellular matrix proteins. The tissue-specific heterogeneity in glycan moieties of dystroglycan and the exact functional roles of glycan moieties in cell adhesion remain to be established.
	Tamao Endo (Department of Glycobiology, Tokyo Metropolitan Institute of Gerontology)
	References (1) Ervasti, JM, Ohlendeick, K, Kahl, SD, Gaver, MG, Campbell, KP : Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature 345, 315-319, 1990 (2) Chiba, A, Matsumura, K, Yamada, H, Inazu, T, Shimizu, T, Kusunoki, S, Kanazawa, I, Kobata, A, Endo, T : Structures of sialylated O-linked oligosaccharides of bovine peripheral nerve alpha-dystroglycan : The role of a novel O-mannosyl type oligosaccharide in the binding with laminin. J. Biol. Chem. 272, 2156-2162, 1997 (3) Williamson, RA, Henry, MD, Daniels, KJ, Hrstka, RF, Lee, JC, Sunada, Y, Ibraghimov-Beskrovnaya, O, Campbell, KP : Dystroglycan is essential for early embryonic development : disruption of Reichert's membrane in Dag1-null mice. Human Molec. Gene 6, 831-841, 1997
Jun.15, 1998