Dystroglycan Versatility

cytoskeleton, thus stabilizing the muscle as it alternately Martin E. Hemler Dana-Farber Cancer Institute contracts and relaxes. In particular, the a-dystroglycan protein binds to the extracellular matrix protein Boston, Massachusetts 02115 laminin-2, while b-dystroglycan spans the membrane and links directly to dystrophin, and other cytoskeletal proteins in the dystrophin family (Figure 1A). These in Dystroglycan, a central component of the skeletal musturn link to other cytoskeletal and signaling proteins cle dystrophin glycoprotein complex (DGC), plays a key (e.g., syntrophin proteins), and to the actin cytoskeleton. role in maintaining normal muscle function. Initially Also, muscle dystroglycan and dystrophin are part of a encoded as a single protein, dystroglycan undergoes larger complex that contains the four 35–50 kDa sarcoposttranslational cleavage to form a-dystroglycan, a glycan proteins (a, b, g, d), as well as the 25 kDa sarcosperipheral membrane protein, and b-dystroglycan, a pan protein, each of uncertain function. The sarcoglytransmembrane protein. Dystroglycan is currently best cans each contain one transmembrane domain, while known for its functions in muscle. However, dystroglysarcospan contains four transmembrane domains. It is can is also widely expressed on nonmuscle cells, and not yet known if sarcospan or any of the sarcoglycans its functions there have been less well studied. Three directly interact with dystroglycan. Mutations in dysnew functions for dystroglycan have now emerged, each trophin, sarcoglycans, and laminin-2 each give rise to involving dystroglycan on nonmuscle cells. As indicated different forms of muscular dystrophy (Campbell, 1995). by Henry and Campbell (1998), dystroglycan may be However, mutations in dystroglycan have not been asrequired for cell-driven assembly of extracellular matrix sociated with muscular dystrophy, presumably because proteins (e.g., laminin-1, collagen IV, and perlecan) into it has many critical functions in nonmuscle cells (see basement membranes. In another study, Cao et al. below). (1998) found that dystroglycan is bound directly by sevIn muscle, dystroglycan also plays a specialized role in eral types of arenaviruses and is necessary for virus neuromuscular junctions (Figure 1B). Here dystroglycan infection. Moreover, Rambukkana et al. (1998) have may bind to agrin, a heparan sulfate proteoglycan indemonstrated that Mycobacterium leprae, complexed volved in synaptic specialization during neuromuscular with laminin-2, utilizes a-dystroglycan as a target for junction development. Agrin contains three laminin-type entry into peripheral nerve Schwann cells. G (LG) domains at its COOH terminus and uses these The role of dystroglycan in skeletal muscle cells can to bind to dystroglycan, while the amino-terminal end be briefly summarized as follows. In muscle fibers, the of agrin binds to various forms of laminin, including associated a and b subunits of dystroglycan play a central role in linking the extracellular matrix with the actin laminin-1, laminin-2, and laminin-4 (Denzer et al., 1998).