Dystrophine

Dystrophin Structure and Glycoprotein Complex

The dystrophin molecules are concentrated over the Z-bands of the muscle, where they form a strong link between the actin filaments of the intracellular contractile apparatus and the extracellular connective tissue matrix.

It is believed that abnormalities in the dystrophin-associated protein complex compromise sarcolemma integrity, particularly with sustained contractions.

When this disruption in integrity occurs, functional dystrophin protein is not made, and Duchenne muscular dystrophy (DMD) Opens in new window is the outcome.

The skeletal muscle isoform of dystrophin is a rodlike cytoskeletal protein localized to the inner surface of the skeletal muscle plasma membrane, the inner layer of the sarcolemma. It forms part of the dystrophin-glycoprotein complex (DGC) linking the cytoskeleton and the extracellular matrix.

The DGC is also called the dystrophin-associated protein complex (DAP), as not all proteins in the complex are glycosylated (Ozawa, 2004). However, this entry uses the term dystrophin-glycoprotein complex (DGC) to include all proteins in the complex.

The specific function(s) of dystrophin and the DGC are not completely elucidated, although it is believed that they could serve both mechanical and signaling roles (Durbeej & Campbell, 2002).

The absence of dystrophin could render the membrane susceptible to mechanical injury, leaky to Ca²⁺, or susceptible to disrupted signaling. These effects alone or in combination could dramatically disrupt muscle function.

Dystrophin-deficient muscle is characterized by increased permeability to endogenous macromolecules flowing out of and into the muscle cell. A classical marker for DMD is an elevated serum muscle creatine kinase concentration (Blake et al., 2002).

Protein and Glycoprotein Complex

Dystrophin protein is expressed in both invertebrates and vertebrates.

Vertebrate dystrophin is located at the cytoplasmic membrane of skeletal, cardiac, and smooth muscle; at the skeletal myotendinus junction; and at synapses in the central nervous system (Roberts, 2001).

The 427 kDa cytoskeletal protein dystrophin is composed of 3,685 amino acids (Kapsa et al., 2003). It is a member of the β–spectrin/α-actinin protein family, which is characterized by an amino-terminal actin-binding domain.

Dystrophin has four separate regions:

1. an amino-terminal actin-binding domain,
2. a central rod domain,
3. a cysteine-rich domain, and
4. a carboxyl-terminal domain (Blake et al., 2002).

The cysteine-rich domain may be the most critical because it interacts with the intracellular tail of β-dystroglycan, which links dystrophin to the sarcolemma membrane and preserves the entire DGC (Roberts, 2001).

The carboxyl-terminal binds additional proteins of the DGC.

Dystrophin represents about 5% of surface-associated sarcolemmal cytoskeletal proteins, and is considered a key structural element in the muscle fiber in that it links cytoskeletal actin to the DGC, which in turn forms a connection through the sarcolemma membrane to the basal lamina.

The dystrophin-glycoprotein complex (DGC) along with additional proteins forms riblike lattices on the cytoplasmic face of the sarcolemma, known as costameres, that facilitate force transmission between active and nonactive fibers.

This complex of proteins also likely acts as a signaling conduit between the outside and inside of the fiber (Lapidos et al., 2004).

Dystrophin is also found in abundance in the myotendinous junction and is thought to facilitate the transmission of forces from the muscle fibers to the tendon (Tidall and Law, 1991).

The complete absence of expressed dystrophin in Duchenne muscular dystrophy (DMD) Opens in new window leads to the loss of the DGC and thus a disrupted costameric lattice (Williams and Bloch, 1999).

Loss of the key structural DGC elements results in the characteristic progressive muscle degradation seen in Duchenne muscular dystrophy (DMD), the mechanisms of which are still not clearly defined.

The dystrophin-glycoprotein complex (DGC) is made up of several subcomplexes, including the dystroglycan complex and the sarcoglycan: sarcospan complex, and the peripheral proteins of the cytoplasmic dystrophin-containing domain.

The amino or N-terminal of dystrophin binds cytoskeletal actin, and its carboxyl- or C-terminal region binds the dystroglycan complex.

The dystroglycan complex is composed of α- and β-Dystroglycan, an integral membrane protein, interacts with dystrophin in the cytosol and with α-dystroglycan, which in turn binds to laminin-2 in the basal lamina.

The sarcoglycan:sarcospan complex, composed of α, β, γ, and δ sarcoglycans and sarcospan, is important for stabilizing the dystroglycan complex in the sarcolemma (Blake et al., 2002).

In muscle, the cytoplasmic dystrophin-containing domain contains α-dystrobrevin that binds directly to dystrophin. Β-Dystrobrevin is found in the DGC of nonmuscle tissues.

Another component of this domain is the syntrophins, adapter proteins that link membrane-associated proteins, dystrophin, and dystrobrevin to the DGC. Associated with the syntrophins is neuronal nitric oxide synthase.

Several other proteins with less well defined functions are associated with the complex, including syncoilin, biglycan, and filamin-2 (Roberts, 2001). Absence of various DGC components leads to other muscular dystrophies (e.g. limb-girdle).