Enhanced laminin binding by α-dystroglycan after enzymatic deglycosylation

Combs, Ariana C.; Ervasti, James M.

doi:10.1042/bj20050375

Cited by 71 publications

(69 citation statements)

References 38 publications

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“…S8). Although the enzymatic activities of LARGE remain to be characterized, one report suggests that an unidentified anionic modification on α-dystroglycan may supply the functional groups needed for ligand-binding activity (25). Interestingly, the binding of laminin α1 to α-dystroglycan depends on clusters of basic amino acid residues located on the surfaces of its LG domains (26).…”

Section: Discussionmentioning

confidence: 99%

Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection

Hara

Kanagawa

Kunz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

107

109

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α-dystroglycan is a highly O-glycosylated extracellular matrix receptor that is required for anchoring of the basement membrane to the cell surface and for the entry of Old World arenaviruses into cells. Like-acetylglucosaminyltransferase (LARGE) is a key molecule that binds to the N-terminal domain of α-dystroglycan and attaches ligand-binding moieties to phosphorylated O-mannose on α-dystroglycan. Here we show that the LARGE modification required for laminin-and virus-binding occurs on specific Thr residues located at the extreme N terminus of the mucin-like domain of α-dystroglycan. Deletion and mutation analyses demonstrate that the ligand-binding activity of α-dystroglycan is conferred primarily by LARGE modification at Thr-317 and -319, within the highly conserved first 18 amino acids of the mucin-like domain. The importance of these paired residues in laminin-binding and clustering activity on myoblasts and in arenavirus cell entry is confirmed by mutational analysis with full-length dystroglycan. We further demonstrate that a sequence of five amino acids, Thr 317 ProThr 319 ProVal, contains phosphorylated O-glycosylation and, when modified by LARGE is sufficient for laminin-binding. Because the N-terminal region adjacent to the paired Thr residues is removed during posttranslational maturation of dystroglycan, our results demonstrate that the ligand-binding activity resides at the extreme N terminus of mature α-dystroglycan and is crucial for α-dystroglycan to coordinate the assembly of extracellular matrix proteins and to bind arenaviruses on the cell surface.

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Section: Discussionmentioning

confidence: 99%

Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection

Hara

Kanagawa

Kunz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

107

109

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“…Using CHO CELL mutants, Patnaik and Stanley have shown that LARGE does not require sialic acid, galactose or fucose to glycosylate α-dystroglycan. 59 Similarly, Combs and Ervasti have shown that enzymatic removal of sialic acid, galactose and N-acetylglucosamine from α-dystroglycan actually stimulates its binding to laminin, 60 much as LARGE overexpression does. 57 Again, this evidence indicates that these carbohydrates are not synthesized by LARGE.…”

Section: Dystroglycanopathy-gene Function: Some Mysteries Remainmentioning

confidence: 97%

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Martin

2006

Nat Rev Neurol

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SUMMARYRecent studies have defined a group of muscular dystrophies, now termed the dystroglycanopathies, as novel disorders of glycosylation. These conditions include Walker-Warburg syndrome, muscleeye-brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I. Although clinical findings can be highly variable, dystroglycanopathies are all characterized by cortical malformations and ocular defects at the more severe end of the clinical spectrum, in addition to muscular dystrophy. All of these disorders are defined by the underglycosylation of α-dystroglycan. Defective glycosylation of dystroglycan severs the link between this important cell adhesion molecule and the extracellular matrix, thereby contributing to cellular pathology. Recent experiments indicate that glycosylation might not only define forms of muscular dystrophy but also provide an avenue to the development of therapies for these disorders.

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“…In these disorders, ␣-DG lacks laminin-binding activity (17); therefore, the tetrasaccharide plays an important role in the post-translational maturation of ␣-DG as a laminin receptor. On the other hand, recent studies have suggested that the Neu5Ac-␣2,3-Gal-␤1,4-GlcNAc branch on O-mannose per se is not likely the lamininbinding glycan of ␣-DG (12,18).…”

Section: Dystroglycan (Dg)mentioning

confidence: 99%

Absence of Post-phosphoryl Modification in Dystroglycanopathy Mouse Models and Wild-type Tissues Expressing Non-laminin Binding Form of α-Dystroglycan

Kuga

Kanagawa

Sudo

et al. 2012

Journal of Biological Chemistry

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Background:The biosynthetic pathway for the ligand-binding moiety of ␣-dystroglycan, defects in which cause dystroglycanopathy, remains unclear. Results:The phosphodiester-linked moiety on O-mannose is absent in dystroglycanopathy models and in wild-type lung and testis. Conclusion: Post-phosphoryl modification is a key determinant of the functional expression of ␣-dystroglycan as a laminin receptor. Significance: This work expands our understanding of the molecular mechanism of a unique post-translational modification.

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Enhanced laminin binding by α-dystroglycan after enzymatic deglycosylation

Cited by 71 publications

References 38 publications

Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection

Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Absence of Post-phosphoryl Modification in Dystroglycanopathy Mouse Models and Wild-type Tissues Expressing Non-laminin Binding Form of α-Dystroglycan

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