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 journalArticle

215 Citations (Scopus)

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
Externally publishedYes

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Dystroglycans
Molecular recognition
Glycosylation
Muscle
Mucins
Muscles
Laminin Receptors
Glycosyltransferases
Dystrophin
Muscular Dystrophies
Biosynthetic Pathways
Neurology
Post Translational Protein Processing
Glycoproteins
Central Nervous System
Genes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Kanagawa, M., Saito, F., Kunz, S., Yoshida-Moriguchi, T., Barresi, R., Kobayashi, Y. M., ... 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

Molecular recognition by LARGE is essential for expression of functional dystroglycan. / Kanagawa, Motoi; Saito, Fumiaki; Kunz, Stefan; Yoshida-Moriguchi, Takako; Barresi, Rita; Kobayashi, Yvonne M.; Muschler, John; Dumanski, Jan P.; Michele, Daniel E.; Oldstone, Michael B A; Campbell, Kevin P.

In: Cell, Vol. 117, No. 7, 25.06.2004, p. 953-964.

Research output: Contribution to journalArticle

Kanagawa, M, Saito, F, Kunz, S, Yoshida-Moriguchi, T, Barresi, R, Kobayashi, YM, Muschler, J, Dumanski, JP, Michele, DE, Oldstone, MBA & Campbell, KP 2004, 'Molecular recognition by LARGE is essential for expression of functional dystroglycan', Cell, vol. 117, no. 7, pp. 953-964. https://doi.org/10.1016/j.cell.2004.06.003
Kanagawa M, Saito F, Kunz S, Yoshida-Moriguchi T, Barresi R, Kobayashi YM et al. Molecular recognition by LARGE is essential for expression of functional dystroglycan. Cell. 2004 Jun 25;117(7):953-964. https://doi.org/10.1016/j.cell.2004.06.003
Kanagawa, Motoi ; Saito, Fumiaki ; Kunz, Stefan ; Yoshida-Moriguchi, Takako ; Barresi, Rita ; Kobayashi, Yvonne M. ; Muschler, John ; Dumanski, Jan P. ; Michele, Daniel E. ; Oldstone, Michael B A ; Campbell, Kevin P. / Molecular recognition by LARGE is essential for expression of functional dystroglycan. In: Cell. 2004 ; Vol. 117, No. 7. pp. 953-964.
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