Abstract
Four unique transmembrane glycoproteins comprise the sarcoglycan complex in striated muscle. The sarcoglycan complex contributes to maintenance of sarcolemma integrity. A shared feature of four types of autosomal recessive limb girdle muscular dystrophy (LGMD) is that mutations in a single sarcoglycan gene result in the loss of all sarcoglycans at the sarcolemma. The mechanism of destabilization is unknown. We report here our findings of sarcoglycan complex biosynthesis in a heterologous cell system. We demonstrate that the sarcoglycans are glycosylated and assemble into a complex that resides in the plasma membrane. Complex assembly was dependent on the simultaneous synthesis of all four sarcoglycans. Mutant sarcoglycans block complex formation and insertion of the sarcoglycans into the plasma membrane. This constitutes the first biochemical evidence to support the idea that the molecular defect in sarcoglycan-deficient LGMD is because of aberrant sarcoglycan complex assembly and trafficking, which leads to the absence of the complex from the sarcolemma.
Highlights
Four unique transmembrane glycoproteins comprise the sarcoglycan complex in striated muscle
The dystrophin-glycoprotein complex (DGC) consists of dystrophin, the syntrophins, ␣- and -dystroglycan, and sarcoglycan, which is composed of four distinct transmembrane glycoproteins named ␣, , ␥, and ␦-sarcoglycan (SG)
Our work demonstrated that the sarcoglycan complex is a requisite component of the DGC for stable anchorage of ␣-dystroglycan to the extracellular face of the sarcolemma, as well as maintenance of an intact sarcolemma
Summary
(Received for publication, August 18, 1998, and in revised form, October 9, 1998). From the Howard Hughes Medical Institute, Department of Physiology and Biophysics, and Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242. Mutant sarcoglycans block complex formation and insertion of the sarcoglycans into the plasma membrane This constitutes the first biochemical evidence to support the idea that the molecular defect in sarcoglycan-deficient LGMD is because of aberrant sarcoglycan complex assembly and trafficking, which leads to the absence of the complex from the sarcolemma. Mutant sarcoglycan constructs engineered to recapitulate known human mutations were found to abrogate sarcoglycan complex assembly and targeting to the plasma membrane These results strongly suggest that the molecular defect in sarcoglycan-deficient LGMD results from the aberrant assembly and trafficking of the sarcoglycan complex to its final destination, the. These results provide compelling support for the idea that sarcoglycan complex assembly requires concomitant synthesis of all four sarcoglycans
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