Mutations in sarcoglycans have been reported to cause autosomal-recessive limb-girdle muscular dystrophies. In skeletal and cardiac muscle, sarcoglycans are assembled into a complex on the sarcolemma from four subunits (alpha, beta, gamma, delta). In this report, we present a detailed structural analysis of sarcoglycans using deletion study, limited proteolysis and co-immunoprecipitation. Our results indicate that the extracellular regions of sarcoglycans consist of distinctive functional domains connected by proteinase K-sensitive sites. The N-terminal half domains are required for sarcoglycan interaction. The C-terminal half domains of beta-, gamma- and delta-sarcoglycan consist of a cysteine-rich motif and a previously unrecognized conserved sequence, both of which are essential for plasma membrane localization. Using a heterologous expression system, we demonstrate that missense sarcoglycan mutations affect sarcoglycan complex assembly and/or localization to the cell surface. Our data suggest that the formation of a stable complex is necessary but not sufficient for plasma membrane targeting. Finally, we provide evidence that the beta/delta-sarcoglycan core can associate with the C-terminus of dystrophin. Our results therefore generate important information on the structure of the sarcoglycan complex and the molecular mechanisms underlying the effects of various sarcoglycan mutations in muscular dystrophies.
"Interestingly, these three mutations are localized in the region adjacent to the transmembrane domain, suggesting that physical constraints due to membrane anchoring may impair the recognition by ERQC. In addition, this region was noticed to be important for interaction of SGs with each other, especially β-SG with δ-SG and α-SG with γ-SG [Chen, et al., 2006]. Therefore, it is possible that improper SGs interactions lead to impairment of one of the nonstructural function of the SGs complex, generating sarcoglycanopathy by a pathological mechanism other than destabilization of the complex. "
[Show abstract][Hide abstract] ABSTRACT: Sarcoglycanopathies (SGP) are a group of autosomal recessive muscle disorders caused by primary mutations in one of the four sarcoglycan genes. The sarcoglycans (α-, β-, γ-, and δ-sarcoglycan) form a tetrameric complex at the muscle membrane that is part of the dystrophin-glycoprotein complex and plays an essential role for membrane integrity during muscle contractions. We previously showed that the most frequent missense mutation in α-sarcoglycan (p.R77C) leads to the absence of the protein at the cell membrane due to its blockade by the endoplasmic reticulum (ER) quality control. Moreover, we demonstrated that inhibition of the ER α-mannosidase I activity using kifunensine could rescue the mutant protein localization at the cell membrane. Here, we investigate 25 additional disease-causing missense mutations in the sarcoglycan genes with respect to intracellular fate and localization rescue of the mutated proteins by kifunensine. Our studies demonstrate that, similarly to p.R77C, 22 of 25 of the selected mutations lead to defective intracellular trafficking of the SGs proteins. Six of these were saved from ER retention upon kifunensine treatment. The trafficking of SGs mutants rescued by kifunensine was associated with mutations that have moderate structural impact on the protein.
Human Mutation 02/2012; 33(2):429-39. DOI:10.1002/humu.21659 · 5.14 Impact Factor
βδ-sarcoglycan core is suggested to link dystrophin through undefined
portions of their intracellular tail (Ref. 29);
five missense mutations reside in the β-sarcoglycan tail and might have either
loss-of-function consequences or simply generate processing mutants; two of these (Q11G and
G56R) cause LGMD in homozygous patients. In the large extracellular domain, the portion of
β-sarcoglycan proximal to the transmembrane domain is thought to be required for
the binding to δ-sarcoglycan (Ref. "
[Show abstract][Hide abstract] ABSTRACT: Sarcoglycanopathies are a group of autosomal recessive muscle-wasting disorders caused by genetic defects in one of four cell membrane glycoproteins, alpha-, beta-, gamma- or delta-sarcoglycan. These four sarcoglycans form a subcomplex that is closely linked to the major dystrophin-associated protein complex, which is essential for membrane integrity during muscle contraction and provides a scaffold for important signalling molecules. Proper assembly, trafficking and targeting of the sarcoglycan complex is of vital importance, and mutations that severely perturb tetramer formation and localisation result in sarcoglycanopathy. Gene defects in one sarcoglycan cause the absence or reduced concentration of the other subunits. Most genetic defects generate mutated proteins that are degraded through the cell's quality control system; however, in many cases, conformational modifications do not affect the function of the protein, yet it is recognised as misfolded and prematurely degraded. Recent evidence shows that misfolded sarcoglycans could be rescued to the cell membrane by assisting their maturation along the ER secretory pathway. This review summarises the etiopathogenesis of sarcoglycanopathies and highlights the quality control machinery as a potential pharmacological target for therapy of these genetic disorders.
Expert Reviews in Molecular Medicine 09/2009; 11:e28. DOI:10.1017/S1462399409001203 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: One of the proposed roles of sarcoglycan is to stabilize dystrophin glycoprotein complexes in muscle sarcolemma. Involvement in signal transduction has also been proposed and abnormalities in some sarcoglycan genes are known to be responsible for muscular dystrophy. While characterization of sarcoglycans in muscle has been performed, little is known about its functions in the non-muscle tissues in which mammalian sarcoglycans are expressed. Here, we investigated temporal and spatial expression patterns of Drosophila beta-sarcoglycan (dScgbeta) during development by immunohistochemistry. In addition to almost ubiquitous expression in various tissues and organs, as seen for its mammalian counterpart, anti-dScgbeta staining data of embryos, eye imaginal discs, and salivary glands demonstrated cytoplasmic localization during S phase in addition to plasma membrane staining. Furthermore we found that subcellular localization of dScgbeta dramatically changes during mitosis through possible association with tubulin. These observations point to a complex role of sarcoglycans in non-muscle tissues.
Cell Structure and Function 02/2006; 31(2):173-80. · 1.68 Impact Factor
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