TY - JOUR
T1 - Molecular recognition by LARGE is essential for expression of functional dystroglycan
AU - Kanagawa, Motoi
AU - Saito, Fumiaki
AU - Kunz, Stefan
AU - Yoshida-Moriguchi, Takako
AU - Barresi, Rita
AU - Kobayashi, Yvonne M.
AU - Muschler, John
AU - Dumanski, Jan P.
AU - Michele, Daniel E.
AU - Oldstone, Michael B.A.
AU - Campbell, Kevin P.
N1 - Funding Information:
We would like to thank Aaron M. Beedle, Daniel Beltrán-Valero De Bernabé and all members of the Campbell laboratory for the critical reading of the manuscript and fruitful discussion. We thank the following for their contribution to this work; Ronald Cohn for the colony of MCK-DG null mice; Shanna Sawatzki and Melissa Hassebrock for expert technical assistance; Charles Lovig and The University of Iowa Hybridoma Facility for preparing monoclonal antibody IIH6; Peter Yurchenco (Robert Johnson Medical School), Lydia Sorokin (University of Erlangen), Stanley Froehner (University of Washington) and Louise Anderson (Novocastra) for providing antibodies; The University of Iowa Gene Transfer Vector Core, supported by NIH P30 DK54759, for adenovirus purification. There are no potential financial conflicts of interest for any of the authors. This work was supported in part by the Muscular Dystrophy Association (K.P.C.) and by US Public Health Service grant AI 45927 (S.K. and M.B.O). K.P.C. is an investigator of the Howard Hughes Medical Institute.
PY - 2004/6/25
Y1 - 2004/6/25
N2 - Reduced ligand binding activity of α-dystroglycan is associated with muscle and central nervous system pathogenesis in a growing number of muscular dystrophies. Posttranslational processing of α-dystroglycan is generally accepted to be critical for the expression of functional dystroglycan. Here we show that both the N-terminal domain and a portion of the mucin-like domain of α-dystroglycan are essential for high-affinity laminin-receptor function. Posttranslational modification of α-dystroglycan by glycosyltransferase, LARGE, occurs within the mucin-like domain, but the N-terminal domain interacts with LARGE, defining an intracellular enzyme-substrate recognition motif necessary to initiate functional glycosylation. Gene replacement in dystroglycan-deficient muscle demonstrates that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly, but to prevent muscle degeneration the expression of a functional dystroglycan through LARGE recognition and glycosylation is required. Therefore, molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan.
AB - Reduced ligand binding activity of α-dystroglycan is associated with muscle and central nervous system pathogenesis in a growing number of muscular dystrophies. Posttranslational processing of α-dystroglycan is generally accepted to be critical for the expression of functional dystroglycan. Here we show that both the N-terminal domain and a portion of the mucin-like domain of α-dystroglycan are essential for high-affinity laminin-receptor function. Posttranslational modification of α-dystroglycan by glycosyltransferase, LARGE, occurs within the mucin-like domain, but the N-terminal domain interacts with LARGE, defining an intracellular enzyme-substrate recognition motif necessary to initiate functional glycosylation. Gene replacement in dystroglycan-deficient muscle demonstrates that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly, but to prevent muscle degeneration the expression of a functional dystroglycan through LARGE recognition and glycosylation is required. Therefore, molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan.
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U2 - 10.1016/j.cell.2004.06.003
DO - 10.1016/j.cell.2004.06.003
M3 - Article
C2 - 15210115
AN - SCOPUS:2942733346
SN - 0092-8674
VL - 117
SP - 953
EP - 964
JO - Cell
JF - Cell
IS - 7
ER -