The dystrophin-associated protein complex.

The lethal muscle-wasting disorder, Duchenne muscular dystrophy, is caused by mutations or deletions in the dystrophin gene. In skeletal and cardiac muscle, dystrophin associates with various proteins to form the dystrophinassociated protein complex (DAPC). The DAPC is thought to play a structural role in linking the actin cytoskeleton to the extracellular matrix, stabilizing the sarcolemma during repeated cycles of contraction and relaxation, and transmitting force generated in the muscle sarcomeres to the extracellular matrix (Petrof et al., 1993). There is also evidence that the DAPC is involved in cell signalling via its interactions with calmodulin, Grb2 and nNOS (Rando, 2001). Various members of the DAPC, such as the sarcoglycans, have already been implicated in a number of muscle diseases, illustrating the vital role this complex plays in the maintenance of muscle integrity. This brief review offers a glimpse of the major known proteins that constitute the DAPC and the defects caused by their absence. Dystrophin The muscle isoform of dystrophin is a 427 kDa protein consisting of an Nterminal actin-binding domain, a central rod-like domain comprising 24 spectrinlike triple helical coiled coils, and a cysteine-rich C-terminus that allows assembly of the DAPC. Dystrophin stretches laterally along F-actin filaments, binding primarily via three sites within the N-terminal region (Norwood et al., 2000) and electrostatically through a cluster of basic repeats (11-17) within the rod domain (Amann et al., 1998). Although remarkable evolutionary conservation exists, with even the C. elegans homologue possessing the same number of spectrin repeats, much of the rod domain appears dispensable and a dystrophin molecule comprising at least eight integral repeats remains relatively Cell Science at a Glance 2801