Disruption of perlecan binding and matrix assembly by post-translational or genetic disruption of dystroglycan function

Department of Physiology and Biophysics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, 400 Eckstein Medical Building, Iowa City, IA 52242, USA.
FEBS Letters (Impact Factor: 3.34). 09/2005; 579(21):4792-6. DOI: 10.1016/j.febslet.2005.07.059
Source: PubMed

ABSTRACT Dystroglycan is a cell-surface matrix receptor that requires LARGE-dependent glycosylation for laminin binding. Although the interaction of dystroglycan with laminin has been well characterized, less is known about the role of dystroglycan glycosylation in the binding and assembly of perlecan. We report reduced perlecan-binding activity and mislocalization of perlecan in the LARGE-deficient Large(myd) mouse. Cell-surface ligand clustering assays show that laminin polymerization promotes perlecan assembly. Solid-phase binding assays provide evidence for the first time of a trimolecular complex formation of dystroglycan, laminin and perlecan. These data suggest functional disruption of the trimolecular complex in glycosylation-deficient muscular dystrophy.

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Available from: Kevin P Campbell, Jul 28, 2015
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    • "The α-DG is modified by three different types of glycans such as: mucin type O-glycosylation, O-mannosylation, and N-glycosylation. The glycosylated α-DG is essential for the protein's ability to bind the laminin globular domaincontaining proteins of the Extracellular Matrix (Kanagawa, 2005). LARGE is required for the generation of functional, properly glycosylated forms of α-DG (Barresi, 2004). "
    Computational Biology and Applied Bioinformatics, 09/2011; , ISBN: 978-953-307-629-4
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    • "Dystroglycan is encoded by a single gene (DAG1) and is cleaved into two proteins, a-dystroglycan (a-DG) and b-dystroglycan (b-DG), by posttranslational processing (Ibraghimov-Beskrovnaya et al., 1992). DGs are central components of the dystrophin– glycoprotein complex (DGC) at the sarcolemma, and a-DG was shown to serve as a cell surface receptor for laminin (Ibraghimov-Beskrovnaya et al., 1992), agrin (Gee et al., 1994; Campanelli et al., 1994), perlecan (Peng et al., 1998; Kanagawa et al., 2005), and neurexin (Sugita et al., 2001). In skeletal muscle , the laminin-a-DG linkage is thought to be critical for plasma membrane stability (recently reviewed in Kanagawa and Toda 2006). "
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    ABSTRACT: Protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) is an enzyme that transfers N-acetylglucosamine to O-mannose of glycoproteins. Mutations of the POMGnT1 gene cause muscle-eye-brain (MEB) disease. To obtain a better understanding of the pathogenesis of MEB disease, we mutated the POMGnT1 gene in mice using a targeting technique. The mutant muscle showed aberrant glycosylation of alpha-DG, and alpha-DG from mutant muscle failed to bind laminin in a binding assay. POMGnT1(-/-) muscle showed minimal pathological changes with very low-serum creatine kinase levels, and had normally formed muscle basal lamina, but showed reduced muscle mass, reduced numbers of muscle fibers, and impaired muscle regeneration. Importantly, POMGnT1(-/-) satellite cells proliferated slowly, but efficiently differentiated into multinuclear myotubes in vitro. Transfer of a retrovirus vector-mediated POMGnT1 gene into POMGnT1(-/-) myoblasts completely restored the glycosylation of alpha-DG, but proliferation of the cells was not improved. Our results suggest that proper glycosylation of alpha-DG is important for maintenance of the proliferative activity of satellite cells in vivo.
    Mechanisms of development 03/2009; 126(3-4):107-16. DOI:10.1016/j.mod.2008.12.001 · 2.24 Impact Factor
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    • "On the external surface of the sarcolemma, components of the dystrophin–glycoprotein complex have been shown to interact with several constituents of the extracellular matrix. Through its incompletely characterized carbohydrate epitopes (Section 2.1), a-dystroglycan has been shown to interact with laminins (Ibraghimov-Beskrovnaya et al., 1992; Ervasti and Campbell, 1993), agrins (Bowe et al., 1994; Campanelli et al., 1994; Gee et al., 1994; Sugiyama et al., 1994), and perlecan (Talts et al., 1999; Peng et al., 1999; Kanagawa et al., 2005), which all bind a-dystroglycan through a conserved G-domain motif (Gee et al., 1993; Hohenester et al., 1999). Laminin-2 is the predominant laminin isoform expressed in striated muscle (Patton et al., 1997) and mutations leading to laminin-2 deficiency cause forms of congenital muscular dystrophy (Xu et al., 1994; Sunada et al., 1994; Helbling-Leclerc et al., 1995). "
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    ABSTRACT: Since its first description in 1990, the dystrophin-glycoprotein complex has emerged as a critical nexus for human muscular dystrophies arising from defects in a variety of distinct genes. Studies in mammals widely support a primary role for the dystrophin-glycoprotein complex in mechanical stabilization of the plasma membrane in striated muscle and provide hints for secondary functions in organizing molecules involved in cellular signaling. Studies in model organisms confirm the importance of the dystrophin-glycoprotein complex for muscle cell viability and have provided new leads toward a full understanding of its secondary roles in muscle biology.
    International Review of Cytology 02/2008; 265:191-225. DOI:10.1016/S0074-7696(07)65005-0 · 9.00 Impact Factor
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