Figure 1. Dystrophin and the dystrophin–glycoprotein complex.

(a) Comparison of the structural domains in full-length dystrophin with those of highly functional miniaturised versions, which have been engineered in response to the limited packaging capacity of delivery vectors for gene therapy. Full-length dystrophin contains four major domains: an N-terminal (NT) cytoskeletal-binding domain, a rod domain composed of 24 spectrin-like repeats (1–24) and four hinge regions (H1–H4), a cysteine-rich (CR) and a C-terminal (CT) domain. The two known actin-binding domains (ABD-1 and ABD-2) are within the N-terminal and rod domains, respectively. The dystroglycan-binding domain (DgBD) is composed of a WW motif (in hinge 4) connected to two EF-hand-like motifs and a ZZ domain (the two EF-hand and ZZ regions comprise the so-called cysteine-rich ‘CR’ domain). Towards the C-terminus is a syntrophin-binding domain (SBD) and a dystrobrevin-binding domain (DbBD). Minidystrophin and microdystrophin retain most of the necessary regions for the signalling and structural roles of dystrophin, as well as the ability to assemble members of the dystrophin–glycoprotein complex (DGC) at the plasma membrane. (b) Important interactions among members of the DGC, many of which are defective in various muscular dystrophies. Within striated muscle fibres, dystrophin binds to cytoskeletal proteins such as filamentous actin (F-actin) at its N-terminal domain. The rod domain encodes a second actin-binding domain in spectrin-like repeats 11–17, and repeats 16–17 also participate in binding to neuronal nitric oxide synthase (nNOS). Although localisation of nNOS has been found to require the presence of both repeats 16–17 and syntrophin, the precise three-dimensional structure of the dystrophin–nNOS complex is speculative (Ref. ⁷⁸). The DgBD anchors β-dystroglycan to dystrophin, and might help to assemble other proteins. The CT domain binds to and localises members of the syntrophin (Syn) and dystrobrevin (Db) protein families. Studies suggest that up to four syntrophins could attach to the DGC at any one time, two to dystrophin and two to dystrobrevin (Ref. ¹⁸⁰). At present it is unclear how many of these syntrophins are attached to nNOS, as it has been shown that syntrophin can also bind to other proteins, such as sodium channels and aquaporin-4 (Refs ¹⁸¹, ¹⁸²). In addition to dystrophin, dystrobrevin is known to bind to another member of the DGC, which has yet to be identified. Abbreviations: Dg, dystroglycan; Sg, sarcoglycan; SSPN, sarcospan.