Function
Dystrophin is a vital protein involved in the structure and function of skeletal and cardiac muscles in the human body. Dystrophin along with the dystrophin- associated glycoprotein complex help to resist the rupture of muscle cells while stretching during muscle contractions. Dystrophin and the dystrophin- associated glycoprotein complex also play a large role in regulation of the 'milieu intérieur [1].
Structural highlights
Dystrophin is a large protein with a molecular weight of 427 kDa. This protein consists of 4 main domains, with the largest central domain making up approximately 75% of its structure. This central, rod- shaped domain is made up of 24 repeating units and is a very highly conserved structure throughout vertebrates. The other domains are the , which is made of 2 sub-domains (), the cysteine- rich domain, and the C terminus domain. The N terminus domain binds to filamentous actin (F- actin), which is a major structural component of the cytoskeleton of muscle fibers. The 2 sub-domains of the N terminus are attached to a hinge, which connects them to the large central domain. The central domain interacts with various membrane phospholipids and with F-actin, n-nitric oxide synthase (nNOS), and microtubules, which are all types of cytosolic proteins. The central domain is interrupted by 2 more hinges. At the fourth hinge, the central domain connects to the cysteine- rich domain, which anchors dystrophin to the intrinsic membrane protein β-dystroglycan. The cysteine- rich domain is then connected to the C terminus domain. The C terminus domain, which contains the , interacts with syntrophin and dystrobrevin, which are cytoplasmic proteins involved in a large protein complex called the dystrophin-associated glycoprotein complex. This complex is located in the extracellular matrix of muscle cells and has a structural function in stabilizing the sarcolemma, which is the outer membrane of muscle fibers. The connection between the extracellular matrix and the cytoskeleton of muscle cells, caused by the linkage of the C terminus domain and the N terminus domain, creates stability during muscle contractions. α-Syntrophin is one of the scaffolding proteins involved in this complex. The carboxy-terminal portion of α-syntrophin binds to dystrophin and other related proteins, leaving the PDZ domain (PSD-95, discs-large, ZO-1) available to recruit other proteins to the dystrophin complex [2]. Dystrophin along with the dystrophin- associated glycoprotein complex help to resist the rupture of muscle cells while stretching during muscle contractions.[3][4]
Connection to Duchenne Muscular Dystrophy
Deficiency of the correctly folded version of this protein leads to a disease called Duchenne Muscular Dystrophy. Duchenne Muscular Dystrophy is an X- linked recessive disorder caused by frame-shift and/or nonsense mutations in the DMD gene, which leads to misfolded and nonfunctional forms of dystrophin in the body. This disorder affects approximately 1 out of every 3500 boys throughout the world. Duchene Muscular Dystrophy is characterized by progressive weakness and degeneration of cardiac and skeletal muscles, which leads to loss of mobilization, cardiomyopathy (weakening of the heart muscle), and eventually death. Onset of symptoms of Duchenne Muscular Dystrophy can begin at only a few years of age, and on average the effected person is wheelchair- bound by age 9.5. No cure for this debilitating disease has been found, but extensive research is being performed to find a way to increase and then keep correct levels of functional dystrophin in people with this disease.[5][6]
