RRC ID 43647
Author Kuga A, Kanagawa M, Sudo A, Chan YM, Tajiri M, Manya H, Kikkawa Y, Nomizu M, Kobayashi K, Endo T, Lu QL, Wada Y, Toda T.
Title Absence of post-phosphoryl modification in dystroglycanopathy mouse models and wild-type tissues expressing non-laminin binding form of α-dystroglycan.
Journal J Biol Chem
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.
Volume 287(12)
Pages 9560-7
Published 2012-3-16
DOI 10.1074/jbc.M111.271767
PII S0021-9258(20)60920-6
PMID 22270369
PMC PMC3308745
MeSH Animals Disease Models, Animal Dystroglycans / genetics Dystroglycans / metabolism* Female Humans Laminin / genetics Laminin / metabolism* Lung / metabolism Male Mice Mice, Transgenic Muscular Dystrophies / genetics Muscular Dystrophies / metabolism* Pentosyltransferases Phosphorylation Protein Binding Protein Processing, Post-Translational Proteins / genetics Proteins / metabolism Testis / metabolism Transferases
IF 4.238
Times Cited 24
Human and Animal Cells