Dystrophin-associated protein complex

The cortical region of many cells is enriched in actin and associated actin-binding proteins, which function in motility, cell shape maintenance, and membrane protein distribution in polarized cells. In some cases, discrete structures anchor actin to the membrane, as is the case for intercellular adherens junctions and cell-substrate focal contacts. In certain special cell types, the fundamental blueprint for an adherens junction is taken to a new structural level, serving as scaffolding for cell-type specific complexes, such as the dystrophin-associated protein complex (DPC) in striated muscle. Although for years morphological studies have described a close association with IF with the actin-rich cortex, recent advances in methods to study protein-protein interactions have provided new insight into the intimate structural and functional relationship between IFs and these membrane domains. 

Fig. 4. Structure of striated muscle costameres and the DPC. A single membrane-associated costamere from a portion of a striated muscle fiber is magnified above to show the components of the dystrophin-associated protein complex that are involved in linking desmin intermediate filaments (IFs) to the muscle cell membrane. Additional actin-associated proteins present at these sites (including vinculin, talin, spectrin, and ankyrin) are not shown here. In addition to components of the DPC, plectin has also been localized to costameres, and likely contributes to linking desmin IFs to actin-associated structures.

Poon, E., Howman, E. V., Newey, S. E., and Davies, K. E. (2002). Association of syncoilin and desmin Linking intermediate filament proteins to the dystrophin-associated protein complex. / Biol. Chem. 277, 3433-3439. 

Crawford, G.E., Faulkner, J.A., Crosbie, R.H., Campbell, K.P., Froehner, S.C., and Chamberlain, J.S., 2000, Assembly of the dystrophin-associated protein complex does not require the dystrophin COOH-terminal domain, J Cell Biol, 150, pp 1399-1410. 

Dystrophin is a rod-shaped cytoplasmic protein that is a vital part of the focal adhesion, or the dystrophin-associated protein complex. Other muscle proteins, such as a-dystrobrevin, syncohn. 

Ehmsen J, Poon E, Davies K. The dystrophin-associated protein complex. J Cell Sci 2002 115 2801-3,... 

A small number of cases have been identified in which there is a deletion of the carboxy-terminus of dystrophin. In these patients, it is common for the mutant protein to localize to the sarcolemma (Bies et al., 1992 Helliwell et al., 1992 Hoffman et al., 1991). These cases are good examples of the importance of the cysteine-rich and C-terminal domains of dystrophin, presumably reflecting the importance of interactions with components of the dystrophin-associated glycoprotein complex. Many single point mutations within dystrophin are also known. 

Suzuki, A., Yoshida, M., Hayashi, K., Mizuno, Y., Hagiwara, Y., and Ozawa, E., 1994, Molecular organization at the glycoprotein-complex-binding site of dystrophin. Three dystrophin-associated proteins bind directly to the carboxy-terminal portion of dystrophin, Eur J Biochem, 220, pp 283—292. 

Functionally, dystrophin is associated with a glycoprotein complex embedded within the sarcolemma, where it acts to help maintain the shape and integrity of each myocyte and is also involved with cell signalling. Boys with DMD typically have less than 5% of the normal amount of functionally active dystrophin whereas in the less severe BMD there may be more than 20% of the protein present. All muscles are affected so not only movement but also breathing becomes impaired. 

While one end of the dystrophin molecule binds to actin filaments, the C-terminal domain associates with several additional proteins to form a dystrophin-glycoprotein complex (see figure)/1 k Dystrophin is linked directly to the membrane-spanning protein P-dystroglycan, which in the outer membrane surfaces associates with a glycoprotein a-dystroglycan. The latter binds to laminin-2 (Fig. 8-33), a protein that binds the cell to the basal lamina. Four... 

Focal adhesions (in muscle often referred to as costameres) are regions that are associated with the sarcolemma of skeletal muscle fibres and comprise proteins of the dystrophin-glycoprotein complex and vinculin-talin-integrin system. Focal adhesions play both a mechanical and a signalling role, transmitting force from the contractile apparatus to the extracellular matrix in order to stabilise skeletal-muscle fibres during contraction and relaxation. Several focal adhesion constituent proteins have been shown to be defective in muscular dystrophies and cardiomyopathies. 

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