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

Research output: Contribution to journalArticlepeer-review

234 Scopus citations


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
Issue number7
StatePublished - Jun 25 2004
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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