Dystrophin is a very large protein (molecular weight 427 kDa) located at the cytoplasmic face of the sarcolemma membrane of striated, smooth, and cardiac muscle cells and, most specifically, in the transverse tubules of the triadic structure. It represents only about 0.01% of the total skeletal muscle protein present in the tissue (1). Its absence, however, appears to be correlated with the fatal muscle-wasting disease known as Duchenne muscular dystrophy (incidence about 1 in 3500 of live male births). Becker muscular dystrophy, a milder form of muscular dystrophy (incidence about 1 in 35,000 of live male births), is related to defects/deletions in the dystrophin sequence. Muscular dystrophy is not related solely to the absence or mutation of dystrophin, however, because evidence has been presented to show that some membrane glycoproteins that normally interact with native dystrophin are degraded at abnormally high rates in either its absence or when it is mutated. This indicates that dystrophin may bind to and hence stabilize the structures of these dystrophin-associated proteins in vivo. It seems likely that dystrophin’s structural role in muscle and nerve is comparable to that played by ankyrin and spectrin with membrane proteins in kidney, brain, and erythrocytes (1).
Dystrophin is a member of the spectrin superfamily of proteins and has many structural similarities with both spectrin and a-actinin . Each has a central rod domain, as well as globular regions located at the N- and C-termini. Like b-spectrin and a-actinin, the N-terminal domain of dystrophin contains a sequence that has high homology with the actin-binding site in a-actinin (2). C-terminal to the rod domain of dystrophin there is a cysteine-rich region about 150 residues that is somewhat akin to that in a-actinin, followed by a further 420 residues that is unique to dystrophin (1). Two putative calcium-binding sites occur within the C-terminal domain, although the sequences do differ from the consensus EF-Hand Motif, possibly significantly. Most of the defects/deletions in dystrophin that cause clinical symptoms are located within the rod domain; and very few are found in the cysteine-rich or C-terminal domains. These portions of the molecule in vivo provide the site of association with a well-characterized transmembrane protein complex. The C-terminal domain has been modeled as a pair of heptad repeat-containing regions (five and six heptads in length) separated by a proline-rich region (2). The d position in the heptads is largely occupied by leucine residues and is thus reminiscent of the leucine zipper structure. These regions are compatible with the formation of a two-stranded coiled-coil structure composed of parallel chains. These data suggest that dystrophin molecules may form a homodimer, or that dystrophin may form a heterodimer with utrophin (a dystrophin-related molecule). It is also known from electron microscopy that dystrophin molecules can assemble in a staggered manner and that these in turn may assemble further to produce end-to-end aggregates.
The rod domain in dystrophin (length estimates derived from electron microscope studies vary between 100 and 175 nm) consists of about 25 repeats, each about 109 residues long. Significant variations do occur, nonetheless; and although the repeats are homologous to those in spectrin and a-actinin, they are very much less regular, especially with regard to length. Ten of the 25 repeating motifs are largely complete (3), in contrast to the remaining 15 repeats, which lack some part(s) of the three constituent a-helices that comprise the three-a-helix motif (see Spectrin, where details of the conformation adopted are given). It has been proposed that dystrophin contains four proline-rich hinge regions within the rod domain that confer flexibility to the molecule and provide sites sensitive to proteolysis.
