The dystrophin-associated protein complex

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Abstract
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 dystrophin-associated 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. FIG1The muscle isoform of dystrophin is a 427 kDa protein consisting of an N-terminal actin-binding domain, a central rod-like domain comprising 24 spectrin-like 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 functional(Harper et al., 2002). Dystrophin deficiency results in loss of the associated protein complex and severe muscular dystrophy, underscoring the central role that dystrophin plays in assembling and maintaining the link between cytoskeletal actin and the extracellular matrix.The widely expressed α and β dystroglycans make up the core of the DAPC, establishing the transmembrane link between laminin-2 and dystrophin. Both proteins are produced from a single post-translationally modified polypeptide, and are heavily glycosylated prior to being sorted to their respective extracellular and transmembrane locations. These glycosylation patterns are developmentally regulated and largely correlate with the diversity of binding partners in different tissues(Winder, 2001). Total deletion of dystroglycan in mouse is embryonic lethal owing to disruption of formation of the extra-embryonic basement membrane, and the void of naturally occurring mutations or other dystroglycan-associated diseases suggests that its function is indispensable for survival (Williamson et al., 1997). Disrupting the dystroglycan-dystrophin link causes a Duchenne-like phenotype, whereas disruption of the laminin-dystroglycan link causes congenital muscular dystrophy. Defects in post-translational modification of dystroglyan may also be pathogenic, as a nonsense mutation in the glycosyltransferase, Large, is the primary defect in the myodystrophy mouse (Grewal et al.,2001).Five transmembrane proteins, all expressed primarily in skeletal muscle,constitute the sarcoglycan family: α (50 kDa, also called adhalin),β (43 kDa), γ (35 kDa), δ (35 kDa) and ϵ (50 kDa). Theβ, γ and δ sarcoglycans co-purify, with β and δforming an especially tight link, whereas α sarcoglycan may be spatially separated. Dystrophin and γ sarcoglycan can interact directly, andδ sarcoglycan appears to be coordinated to the dystroglycan complex(Chan et al., 1998). Mutations abolishing the expression of any one of the sarcoglycans cause loss of the others from the sarcolemma; the four recessive limb girdle muscular dystrophies 2D, 2E, 2C and 2F are caused by absence of the α, β,γ or δ sarcoglycans, respectively(Bushby, 1999).Sarcospan is a 25 kDa membrane protein with four transmembrane domains and intracellular N- and C-termini, a unique feature for transmembrane proteins of the DAPC (Crosbie et al.,1997). Expression is seen predominantly in skeletal and cardiac muscle, but shorter isoforms exist in other tissues. No human disease is currently known to be associated with sarcospan deficiency, and sarcospan-null mice maintain expression of all sarcoglycans at the sarcolemma and do not develop muscular dystrophy (Lebakken et al., 2000).Alternative splicing produces five α-dystrobrevin isoforms, differing as C-terminal truncations. Three of these are found in muscle, but onlyα-dystrobrevin-2 is abundantly expressed at the sarcolemma. This isoform contains two tandem α-helical syntrophin-binding sites, which may be alternatively spliced to modulate the stoichiometry of syntrophin association with the DAPC (Newey et al.,2000). As dystrobrevin contains several tyrosine kinase consensus sites, protein-protein interactions may also be regulated by tyrosine phosphorylation. Dystrobrevin associates with dystrophin via coiled-coil interactions, but an independent link with the sarcoglycan/sarcospan complex might also exist as dystrobrevin and syntrophin can bind to the DAPC in the absence of the C-terminal region of dystrophin(Crawford et al., 2000). Intriguingly, dystrobrevin-knockout mice present with a DMD-like phenotype while retaining the DAPC and sarcolemmal integrity. Loss of dystrobrevin is expected to disrupt the syncoilin-mediated link between the DAPC and desmin intermediate filaments (see below), perhaps contributing to dystrophy. Alternatively, the coordinate reduction of sarcolemmal nNOS that is observed in these knockouts suggests that signalling defects may be at fault(Grady et al., 1999).All three of the 58 kDa syntrophin isoforms are found at the neuromuscular junction in...