Differential Vicia villosa Agglutinin Reactivity Identifies Three Distinct Dystroglycan Complexes in Skeletal Muscle

McDearmon, Erin L.; Combs, Ariana C.; Ervasti, James M.

doi:10.1074/jbc.m103843200

Cited by 30 publications

(20 citation statements)

References 43 publications

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“…Consistent with previous studies from several labs (15,17,30,31), neuraminidase treatment of C2C12 myotubes caused an ϳ4-fold increase in the number of clusters observed in comparison with untreated myotubes (Fig. 6).…”

Section: ␣-Dystroglycan Core 1 Glycans In Achr Clusteringsupporting

confidence: 80%

“…Cells were rinsed twice with media and fixed and stained as described above. Fluorescence images were collected with a Bio-Rad MRC 1000 confocal microscope (Keck Center for Biological Imaging), or Zeiss CFL 25 fluorescence microscope using a 40ϫ oil immersion objective and the number of AChR quantitated as previously described (17). All images were re-sized and cropped using Adobe Photoshop 5.0 and imported into CorelDraw 10 for figure preparation.…”

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confidence: 99%

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Core 1 Glycans on α-Dystroglycan Mediate Laminin-induced Acetylcholine Receptor Clustering but Not Laminin Binding

McDearmon

Combs

Ervasti

2003

Journal of Biological Chemistry

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Although unique O-linked oligosaccharides on ␣-dystroglycan are important for binding to a variety of extracellular ligands, the function(s) of more generic carbohydrate structures on ␣-dystroglycan remain unclear. Recent studies suggest a role for glycoconjugates bearing the core 1 disaccharide Gal␤(1-3)GalNAc in acetylcholine receptor (AChR) clustering on the surface of muscle cells. Here, we report experiments demonstrating that the core 1-specific lectin jacalin almost completely abrogated laminin-induced AChR clustering in C2C12 myotubes and that ␣-dystroglycan was the predominant jacalin-binding protein detected in C2C12 myotube lysates. Although jacalin likely inhibited laminin-induced AChR clustering by directly binding to ␣-dystroglycan, jacalin had no effect on laminin binding to the myotube surface or to ␣-dystroglycan. Like jacalin, peanut agglutinin lectin also binds the core 1 disaccharide but not when it is terminally sialylated as expressed on ␣-dystroglycan. We show that C2C12 ␣-dystroglycan bound to peanut agglutinin only after digestion with neuraminidase. Simultaneous treatment of myotubes with neuraminidase and endo-O-glycosidase diminished ␣-dystroglycan binding to peanut agglutinin and inhibited neuraminidase-induced AChR clustering. We conclude that sialylated core 1 oligosaccharides of ␣-dystroglycan are important for laminin-induced AChR clustering and that their function in this process is distinct from the established role of ␣-dystroglycan oligosaccharides in laminin binding.

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Section: ␣-Dystroglycan Core 1 Glycans In Achr Clusteringsupporting

confidence: 80%

mentioning

confidence: 99%

Core 1 Glycans on α-Dystroglycan Mediate Laminin-induced Acetylcholine Receptor Clustering but Not Laminin Binding

McDearmon

Combs

Ervasti

2003

Journal of Biological Chemistry

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“…These results suggest that neither ␣1-syntrophin, or any other dystrophin-associated protein contributed to the actin binding characteristics previously measured for native dystrophin-glycoprotein complex (5). A considerable amount of syntrophins is recovered in the soluble fraction after muscle homogenization (13) and does not copurify with the dystrophin-glycoprotein complex (22). Furthermore, the soluble syntrophins were shown to be able to interact with actin and inhibit actin binding to myosin.…”

Section: Discussionmentioning

confidence: 64%

Dystrophin and Utrophin Bind Actin through Distinct Modes of Contact

Rybakova

Humston

Sonnemann

et al. 2006

Journal of Biological Chemistry

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108

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This study was designed to define the molecular epitopes of dystrophin-actin interaction and to directly compare the actin binding properties of dystrophin and utrophin. According to our data, dystrophin and utrophin both bound alongside actin filaments with submicromolar affinities. However, the molecular epitopes involved in actin binding differed between the two proteins. In utrophin, the amino-terminal domain and an adjacent string of the first 10 spectrin-like repeats more fully recapitulated the activities measured for full-length protein. The homologous region of dystrophin bound actin with low affinity and near 1:1 stoichiometry as previously measured for the isolated amino-terminal, tandem (CH) domain. In contrast, a dystrophin construct including a cluster of basic spectrin-like repeats and spanning from the amino terminus through repeat 17, bound actin with properties most similar to full-length dystrophin. Dystrophin and utrophin both stabilized preformed actin filaments from forced depolymerization with similar efficacies but did not appear to compete for binding sites on actin. We also found that dystrophin binding to F-actin was markedly sensitive to increasing ionic strength, although utrophin binding was unaffected. Although dystrophin and utrophin are functionally homologous actin-binding proteins, these results indicate that their respective modes of contact with actin filaments are markedly different. Finally, we reassessed the abundance of dystrophin in striated muscle using full-length protein as the standard and measured greater than 10-fold higher values than previously reported.Dystrophin and utrophin are homologous proteins with similar interacting partners. By providing a link between the actin cytoskeleton and the extracellular matrix, dystrophin functions to maintain the integrity of the cell membrane during muscle contraction. Consequently, genetic ablation of dystrophin leads to increased fragility in the muscle membrane and results in the pathologies observed in Duchenne and Becker muscular dystrophies and some forms of cardiomyopathy. The functional role of utrophin is not completely understood. However, utrophin overexpression in the dystrophin-deficient mdx mouse has been shown to correct all known parameters of the dystrophic phenotype (1). Notably, utrophin overexpression rescued the mechanical linkage between costameric actin and the sarcolemma of the dystrophin-deficient mdx mouse muscle (2).Like other members of the spectrin superfamily of proteins, both dystrophin and utrophin interact with actin via the amino-terminal tandem calponin homology (CH) 2 actin-binding domain (3-6). Additionally, in both dystrophin and utrophin, the spectrin-like repeats of the rod domain have been shown to contribute to actin binding. According to our recent study, the first 10 spectrin-like repeats of utrophin increase the affinity and capacity of its amino-terminal domain for actin (7). The actin binding activity of the homologous region of dystrophin has not been investigated yet. However,...

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“…17 Differential glycosylation of ADG confers tissue-specific functional variability. 18 Structural analysis of the sugars decorating ␣-dystroglycan is limited. One structure that has received attention is the O-mannosyl linked oligosaccharide Neu5Ac(␣2-3)Gal(␤1-4)GlcNAc(␤1-2)Man(␣1-O)-S/T, a class of glycan found on only a very few mammalian proteins, and apparently accounting between 30 and 50% of the total mass of ␣-dystroglycan.…”

Section: Dystroglycan and Its Glycosylationmentioning

confidence: 99%

Muscular dystrophies due to glycosylation defects

Muntoni

Torelli²,

Wells³

et al. 2011

Current Opinion in Neurology

124

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Summary:In the last few years, muscular dystrophies due to reduced glycosylation of alpha-dystroglycan (ADG) have emerged as a common group of conditions, now referred to as dystroglycanopathies. Mutations in six genes (POMT1, POMT2, POMGnT1, Fukutin, FKRP and LARGE) have so far been identified in patients with a dystroglycanopathy. Allelic mutations in each of these genes can result in a wide spectrum of clinical conditions, ranging from severe congenital onset with associated structural brain malformations (Walker Warburg syndrome; muscle-eye-brain disease; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D) to a relatively milder congenital variant with no brain involvement (congenital muscular dystrophy type 1C), and to limb-girdle muscular dystrophy (LGMD) type 2 variants with onset in childhood or adult life (LGMD2I, LGMD2L, and LGMD2N).ADG is a peripheral membrane protein that undergoes multiple and complex glycosylation steps to regulate its ability to effectively interact with extracellular matrix proteins, such as laminin, agrin, and perlecan.Although the precise composition of the glycans present on ADG are not known, it has been demonstrated that the forced overexpression of LARGE, or its paralog LARGE2, is capable of increasing the glycosylation of ADG in normal cells. In addition, its overexpression is capable of restoring dystroglycan glycosylation and laminin binding properties in primary cell cultures of patients affected by different genetically defined dystroglycanopathy variants.These observations suggest that there could be a role for therapeutic strategies to overcome the glycosylation defect in these conditions via the overexpression of LARGE.

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Differential Vicia villosa Agglutinin Reactivity Identifies Three Distinct Dystroglycan Complexes in Skeletal Muscle

Cited by 30 publications

References 43 publications

Core 1 Glycans on α-Dystroglycan Mediate Laminin-induced Acetylcholine Receptor Clustering but Not Laminin Binding

Core 1 Glycans on α-Dystroglycan Mediate Laminin-induced Acetylcholine Receptor Clustering but Not Laminin Binding

Dystrophin and Utrophin Bind Actin through Distinct Modes of Contact

Muscular dystrophies due to glycosylation defects

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