title: Absence of post-phosphoryl modification in dystroglycanopathy mouse models and wild-type tissues expressing non-laminin binding form of α-dystroglycan.
abstract: α-Dystroglycan (α-DG) is a membrane-associated glycoprotein that interacts with several extracellular matrix proteins, including laminin and agrin. Aberrant glycosylation of α-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-α2,3-Gal-β1,4-GlcNAc-β1,2-Man) and a phosphodiester-linked modification on O-mannose play important roles in the laminin binding activity of α-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 α-DG. Furthermore, we have found that the glycosylation status of α-DG in lung and testis is minimally affected by defects in fukutin, LARGE, or FKRP. α-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 α-DG functional expression as a laminin receptor in normal tissues and cells.
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuga
authors.forename: Motoi
authors.initials: M
authors.lastname: Kanagawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sudo
authors.forename: Yiumo Michael
authors.initials: YM
authors.lastname: Chan
authors.forename: Michiko
authors.initials: M
authors.lastname: Tajiri
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Manya
authors.forename: Yamato
authors.initials: Y
authors.lastname: Kikkawa
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Nomizu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Tamao
authors.initials: T
authors.lastname: Endo
authors.forename: Qi L
authors.initials: QL
authors.lastname: Lu
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Wada
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism*; D010430:Pentosyltransferases; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D014166:Transferases
chemical_list: D007797:Laminin; D011506:Proteins; C102645:laminin alpha 2; D049030:Dystroglycans; C084098:laminin A; D014166:Transferases; C499093:Fkrp protein, mouse; D010430:Pentosyltransferases