Abstract
The systematic bioanalytical characterization of the protein product of the DMD gene, which is defective in the pediatric disorder Duchenne muscular dystrophy, led to the discovery of the membrane cytoskeletal protein dystrophin. Its full-length muscle isoform Dp427-M is tightly linked to a sarcolemma-associated complex consisting of dystroglycans, sarcoglyans, sarcospan, dystrobrevins and syntrophins. Besides these core members of the dystrophin–glycoprotein complex, the wider dystrophin-associated network includes key proteins belonging to the intracellular cytoskeleton and microtubular assembly, the basal lamina and extracellular matrix, various plasma membrane proteins and cytosolic components. Here, we review the central role of the dystrophin complex as a master node in muscle fibers that integrates cytoskeletal organization and cellular signaling at the muscle periphery, as well as providing sarcolemmal stabilization and contractile force transmission to the extracellular region. The combination of optimized tissue extraction, subcellular fractionation, advanced protein co-purification strategies, immunoprecipitation, liquid chromatography and two-dimensional gel electrophoresis with modern mass spectrometry-based proteomics has confirmed the composition of the core dystrophin complex at the sarcolemma membrane. Importantly, these biochemical and mass spectrometric surveys have identified additional members of the wider dystrophin network including biglycan, cavin, synemin, desmoglein, tubulin, plakoglobin, cytokeratin and a variety of signaling proteins and ion channels.
Highlights
Following the identification of one of the largest genes in the human genome, the DMD gene [1], and the initial characterization of its full-length protein product [2,3], it became clear that dystrophin exists in a variety of isoforms ranging in molecular mass from approximately 71 to 427 kDa [4]
Since the large Dp427-M isoform was shown to be tightly associated with several glycoproteins in skeletal muscle fibers [6,7,8,9,10,11], it was concluded that dystrophin probably functions as a molecular anchoring system in the subsarcolemmal cytoskeleton [12,13]
Since the discovery of dystrophin over 30 years ago, a large body of scientific evidence has been gathered that strongly supports the idea that the full-length dystrophin isoform Dp427-M forms the core of a supramolecular protein assembly at the sarcolemma
Summary
Following the identification of one of the largest genes in the human genome, the DMD gene [1], and the initial characterization of its full-length protein product [2,3], it became clear that dystrophin exists in a variety of isoforms ranging in molecular mass from approximately 71 to 427 kDa [4]. This article focuses on recent biochemical, proteomic and cell biological investigations aimed at the systematic identification of indirectly associated proteins belonging to the wider dystrophin network This includes crucial members of the extracellular matrix such as biglycan, the surface desmoglein complex, and members of the cytoskeletal network including vimentin, tubulin, desmin and cytokeratin, as well as the cavin–caveolin complex, plakoglobin, ion channels and various signaling proteins. These newer findings have modified the initial view of dystrophin being a purely structural component that functions as a molecular anchor and shock absorber in the membrane cytoskeleton. The dystrophin complex has been implicated to provide a master node for cytoskeletal organization and cellular signaling events, which are characterized by the linkage of dystrophin to ion channels, the insulin signaling pathway, nitric oxide-based regulatory processes, kinase signaling pathways and excitation–contraction coupling [36]
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