Absence of post-phosphoryl modification in dystroglycanopathy mouse models and wild-type tissues expressing non-laminin binding form of ?-dystroglycan.

ABSTRACT: ?-Dystroglycan (?-DG) is a membrane-associated glycoprotein that interacts with several extracellular matrix proteins, including laminin and agrin. Aberrant glycosylation of ?-DG disrupts its interaction with ligands and causes a certain type of muscular dystrophy commonly referred to as dystroglycanopathy. It has been reported that a unique O-mannosyl tetrasaccharide (Neu5Ac-?2,3-Gal-?1,4-GlcNAc-?1,2-Man) and a phosphodiester-linked modification on O-mannose play important roles in the laminin binding activity of ?-DG. In this study, we use several dystroglycanopathy mouse models to demonstrate that, in addition to fukutin and LARGE, FKRP (fukutin-related protein) is also involved in the post-phosphoryl modification of O-mannose on ?-DG. Furthermore, we have found that the glycosylation status of ?-DG in lung and testis is minimally affected by defects in fukutin, LARGE, or FKRP. ?-DG prepared from wild-type lung- or testis-derived cells lacks the post-phosphoryl moiety and shows little laminin-binding activity. These results show that FKRP is involved in post-phosphoryl modification rather than in O-mannosyl tetrasaccharide synthesis. Our data also demonstrate that post-phosphoryl modification not only plays critical roles in the pathogenesis of dystroglycanopathy but also is a key determinant of ?-DG functional expression as a laminin receptor in normal tissues and cells.

SUBMITTER: Kuga A 

PROVIDER: S-EPMC3308745 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature