Dystrophin-Glycoprotein Complex: Post-translational Processing and Dystroglycan Function* 210

The dystrophin-glycoprotein complex (DGC) is a multimeric transmembrane protein complex first isolated from skeletal muscle membranes (1). The central protein of the DGC is dystroglycan (Fig. 1). In addition to skeletal muscle, dystroglycan is strongly expressed in heart and smooth muscle, as well as many non-muscle tissues including brain and peripheral nerve. In vertebrates, dystroglycan is generated from a single gene (DAG1), which is cleaved into a peripheral -dystroglycan protein and a transmembrane -dystroglycan protein (2). At the sarcolemma in muscle, -dystroglycan binds intracellularly to dystrophin, which binds the actin cytoskeleton, and extracellularly to -dystroglycan. -Dystroglycan completes the link from the cytoskeleton to the basal lamina by calcium-dependent binding with high affinity to extracellular matrix proteins (Fig. 1) containing LamG domains, such as laminin (3), neurexin (4), agrin (5–8), and perlecan (9). In addition to dystroglycan and dystrophin, the DGC in muscle cells contains a sarcoglycan complex composed of four sarcoglycan proteins ( , , , ) and sarcospan (1, 10). Intracellularly, the sarcolemma DGC, through dystrophin, interacts with a pair of syntrophins ( 1 and 1) (11) and -dystrobrevin (12). -Syntrophin and -dystrobrevin can interact with nNOS and localize it to the sarcolemma (13, 14). Syntrophin also can interact with aquaporin 4 through a PDZ domain and can stabilize it in the sarcolemma (15). The C-terminal tail of -dystroglycan also contains a PPXY motif that can interact with dystrophin or caveolin 3 (16). The exact function of the entire DGC is not completely determined but it is thought to contribute to the structural stability of the muscle cell membrane during cycles of contraction and relaxation (17). In humans, mutations in dystrophin cause Duchenne and Becker muscular dystrophy, mutations in sarcoglycans in skeletal muscle cause limb-girdle muscular dystrophy, and mutations in 2 laminin cause congenital muscular dystrophy (18). Despite the central role of dystroglycan in the DGC, no primary mutations in dystroglycan have been identified in any human disease. However, mutations in dystrophin do cause a secondary reduction in sarcolemma expression of dystroglycan (2). Disruption of the DAG1 gene in mice results in embryonic lethality, and dystroglycan appears essential for the formation of the basement membrane (Reichert’s membrane) that separates the embryo from the maternal circulation in the mouse (19, 20). Emerging genetic data have shown that mutations in proteins with homology to glycosyltransferases are linked to murine and human muscular dystrophies. Biochemical analysis of muscle biopsies has revealed a convergent role for these proteins in the glycosylation of -dystroglycan, a process that is required for its functional activity. The loss of dystroglycan function by incomplete glycosylation can lead to a variety of clinical symptoms including muscular dystrophy and abnormal central nervous system development and function. Here we review what is known about the biosynthetic pathway of dystroglycan required for its normal structure and function and the new insights into dystroglycan function revealed from the study of mouse models and human patients with incomplete glycosylation-induced “dystroglycanopathies. ” Because the only detected DGC defect in these “dystroglycanopathies” is the disruption of the dystroglycan ligand binding domain, the recent work supports the proposal that the functions of components of the DGC in the sarcolemma of differentiated skeletal muscle are largely to support the integrity and sarcolemma localization of the central extracellular matrix receptor, dystroglycan.