Molecular recognition by LARGE is essential for expression of functional dystroglycan

Motoi Kanagawa, Fumiaki Saito, Stefan Kunz, Takako Yoshida-Moriguchi, Rita Barresi, Yvonne M. Kobayashi, John Muschler, Jan P. Dumanski, Daniel E. Michele, Michael B.A. Oldstone, Kevin P. Campbell

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216 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)953-964
Number of pages12
JournalCell
Volume117
Issue number7
DOIs
StatePublished - Jun 25 2004

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kanagawa, M., Saito, F., Kunz, S., Yoshida-Moriguchi, T., Barresi, R., Kobayashi, Y. M., Muschler, J., Dumanski, J. P., Michele, D. E., Oldstone, M. B. A., & Campbell, K. P. (2004). Molecular recognition by LARGE is essential for expression of functional dystroglycan. Cell, 117(7), 953-964. https://doi.org/10.1016/j.cell.2004.06.003