Specific assembly pathway of sarcoglycans is dependent on beta- and delta-sarcoglycan
Weixing Shi MSc
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Search for more papers by this authorZaili Chen MD
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Search for more papers by this authorJodi Schottenfeld BA
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Search for more papers by this authorRichard C. Stahl BSc
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Search for more papers by this authorLouis M. Kunkel PhD
Howard Hughes Medical Institute and Division of Genetics, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorCorresponding Author
Yiu-Mo Chan PhD
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USASearch for more papers by this authorWeixing Shi MSc
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Search for more papers by this authorZaili Chen MD
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Search for more papers by this authorJodi Schottenfeld BA
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Search for more papers by this authorRichard C. Stahl BSc
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Search for more papers by this authorLouis M. Kunkel PhD
Howard Hughes Medical Institute and Division of Genetics, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA
Search for more papers by this authorCorresponding Author
Yiu-Mo Chan PhD
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USA
Sigfried and Janet Weis Center for Research M.C. 26-11, The Geisinger Clinic, 100 North Academy Avenue, Danville, Pennsylvania 17822, USASearch for more papers by this authorAbstract
Mutations in sarcoglycans (SG) have been reported to cause autosomal-recessive limb-girdle muscular dystrophy (LGMD) and dilated cardiomyopathy. In skeletal and cardiac muscle, sarcoglycans exist as a complex of four transmembrane proteins (α-, β-, γ-, and δ-SG). In this study, the assembly of the sarcoglycan complex was examined in a heterologous expression system. Our results demonstrated that the assembly process occurs as a discrete stepwise process. We found that β-SG appears to play an initiating role and its association with δ-SG is essential for the proper localization of the sarcoglycan complex to the cell membrane. The incorporation of α-SG into the sarcoglycan complex occurs at the final stage by interaction with γ-SG. These findings were supported by chemical cross-linking of endogenous sarcoglycans in cultured myotubes. We have also provided evidence that glycosylation-defective mutations in β-SG and a common mutation in γ-SG (C283Y) disrupt sarcoglycan-complex formation. Our proposed model for the assembly and structure of sarcoglycans should generate important insight into their function in muscle as well as their role in muscular dystrophies and cardiomyopathies. Muscle Nerve 29: 409–419, 2004
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