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ABSTRACT: Alpha-dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix, while beta-dystroglycan is a type I integral membrane protein which anchors alpha-dystroglycan to the cell membrane via the N-terminal extracellular domain. The complex composed of alpha- and beta-dystroglycan is called the dystroglycan complex. Although defects of the dystroglycan gene have not been identified as the primary causes of hereditary diseases in humans, secondary but significant abnormalities of the dystroglycan complex have been revealed in severe muscular dystrophies, including sarcoglycanopathy (LGMD2C, D, E and F). In this study, we investigated proteolytic processing of beta-dystroglycan and its effect on the extracellular matrix-cell membrane linkage in cardiomyopathic hamsters, the model animals of LGMD2F. Compared to normal controls, proteolytic processing of beta-dystroglycan was activated in the skeletal, cardiac and smooth muscles of cardiomyopathic hamsters and this resulted in the partial disruption of the dystroglycan complex in these tissues. These phenomena were observed from the early phase of muscle degeneration process. Our results suggest that proteolytic processing of beta-dystroglycan disrupts the extracellular matrix-cell membrane linkage via the dystroglycan complex and this may play a role in the molecular pathogenesis of muscle degeneration in cardiomyopathic hamsters.
Neuromuscular Disorders 01/2004; 13(10):796-803. · 2.80 Impact Factor
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01/1997;
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ABSTRACT: We have shown previously that α-dystroglycan with a molecular mass of 120 kDa is a Schwann cell receptor of laminin-2, the
endoneurial isoform of laminin comprised of the α2, β1, and γ1 chains. In this paper, we show that Schwann cell α-dystroglycan
is also a receptor of agrin, an acetylcholine receptor-aggregating molecule having partial homology to laminin α chains in
the C terminus. Immunochemical analysis demonstrates that the peripheral nerve isoform of agrin is a 400-kDa component of
the endoneurial basal lamina and is co-localized with α-dystroglycan surrounding the outermost layer of myelin sheath of peripheral
nerve fibers. Blot overlay analysis demonstrates that both endogenous peripheral nerve agrin and laminin-2 bind to Schwann
cell α-dystroglycan. Recombinant C-terminal fragment of the peripheral nerve isoform of agrin also binds to Schwann cell α-dystroglycan,
confirming that the binding site for Schwann cell α-dystroglycan resides in the C terminus of agrin molecule. Furthermore,
the binding of recombinant agrin C-terminal fragment to Schwann cell α-dystroglycan competes with that of laminin-2. All together,
these results indicate that α-dystroglycan is a dual receptor for agrin and laminin-2 in the Schwann cell membrane.
Journal of Biological Chemistry 09/1996; 271(38):23418-23423. · 4.77 Impact Factor
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Hiroki Yamada,
Atsuro Chiba,
Tamao Endo,
Akira Kobata,
Louise V. B. Anderson,
Hisae Hori, Hiroko Fukuta-Ohi,
Ichiro Kanazawa,
Kevin P. Campbell,
Teruo Shimizu,
Kiichiro Matsumura
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ABSTRACT: Dystroglycan is encoded by a single gene and cleaved into two proteins, - and β-dystroglycan, by posttranslational processing. The 120-kDa peripheral nerve isoform of -dystroglycan binds laminin-2 comprised of the 2, β1, and 1 chains. In congenital muscular dystrophy and dy mice deficient in laminin 2 chain, peripheral myelination is disturbed, suggesting a role for the dystroglycan-laminin interaction in peripheral myelinogenesis. To begin to test this hypothesis, we have characterized the dystroglycan-laminin interaction in peripheral nerve. We demonstrate that (1) -dystroglycan is an extracellular peripheral membrane glycoprotein that links β-dystroglycan in the Schwann cell outer membrane with laminin-2 in the endoneurial basal lamina, and (2) dystrophin homologues Dp116 and utrophin are cytoskeletal proteins of the Schwann cell cytoplasm. We also present data that suggest a role for glycosylation of -dystroglycan in the interaction with laminin.
Journal of Neurochemistry 03/1996; 66(4):1518 - 1524. · 4.06 Impact Factor
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ABSTRACT: The dystroglycan complex is a membrane-spanning complex composed of two subunits, α - and &bgr; -dystroglycan. α -dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), whereas &bgr; -dystroglycan is an integral membrane protein which anchors α -dystroglycan to the cell membrane. The dystroglycan complex provides a tight link between the ECM and cell membrane. Dysfunction of the dystroglycan complex has commonly been implicated in the molecular pathogenesis of severe forms of hereditary neuromuscular diseases, including Duchenne muscular dystrophy, Fukuyama-type congenital muscular dystrophy and sarcoglycanopathy (LGMD2C, -D, -E and -F). To begin to clarify the pathway by which the dysfunction of the dystroglycan complex could lead to muscle cell degeneration, we investigated the proteolytic processing of the dystroglycan complex in this study. We demonstrate that (i) a 30 kDa fragment of &bgr; -dystroglycan is expressed in peripheral nerve, kidney, lung and smooth muscle, but not skeletal muscle, cardiac muscle or brain, and (ii) this fragment is the product of proteolytic processing of the extracellular domain of &bgr; -dystroglycan by the membrane-associated matrix metalloproteinase (MMP) activity. Importantly, furthermore, we demonstrate that this processing disintegrates the dystroglycan complex. Our results indicate that the processing of &bgr; -dystroglycan by MMP causes the disruption of the link between the ECM and cell membrane via the dystroglycan complex, which could have profound effects on cell viability. Based on these and previously reported findings, we propose a hypothesis that this processing may play a crucial role in the molecular pathogenesis of sarcoglycanopathy.
