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J. Biol. Chem., Vol. 280, Issue 21, 20851-20859, May 27, 2005

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Mouse Large Can Modify Complex N- and Mucin O-Glycans on -Dystroglycan to Induce Laminin Binding^*

Santosh K. Patnaik and Pamela Stanley

From the Department of Cell Biology, Albert Einstein College of Medicine, New York, New York 10461

The human LARGE gene encodes a protein with two putative glycosyltransferase domains and is required for the generation of functional -dystroglycan (-DG). Monoclonal antibodies IIH6 and VIA4-1 recognize the functional glycan epitopes of -DG that are necessary for binding to laminin and other ligands. Overexpression of full-length mouse Large generated functionally glycosylated -DG in Pro^-5 Chinese hamster ovary (CHO) cells, and the amount was increased by co-expression of protein:O-mannosyl N-acetylglucosaminyltransferase 1. However, functional -DG represented only a small fraction of the -DG synthesized by CHO cells or expressed from an -DG construct. To identify features of the glycan epitopes induced by Large, the production of functionally glycosylated -DG was investigated in several CHO glycosylation mutants. Mutants with defective transfer of sialic acid (Lec2), galactose (Lec8), or fucose (Lec13) to glycoconjugates, and the Lec15 mutant that cannot synthesize O-mannose glycans, all produced functionally glycosylated -DG upon overexpression of Large. Laminin binding and the -DG glycan epitopes were enhanced in Lec2 and Lec8 cells. In Lec15 cells, functional -DG was increased by co-expression of core 2 N-acetylglucosaminyltransferase 1 with Large. Treatment with N-glycanase markedly reduced functionally glycosylated -DG in Lec2 and Lec8 cells. The combined data provide evidence that Large does not transfer to Gal, Fuc, or sialic acid on -DG nor induce the transfer of these sugars to -DG. In addition, the data suggest that human LARGE may restore functional -DG to muscle cells from patients with defective synthesis of O-mannose glycans via the modification of N-glycans and/or mucin O-glycans on -DG.

Received for publication, January 4, 2005 , and in revised form, February 23, 2005.

^* This work was supported by NCI Grant RO1 36434 from the National Institutes of Health (to P. S.) and in part by Albert Einstein Cancer Center Grant PO1 13330. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 1300 Morris Park Ave., New York, NY 10461. Tel.: 718-430-3346; Fax: 718-430-8574; E-mail: stanley{at}aecom.yu.edu.

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