Volume 59 (2017) Issue 2-3 Pages 114-120
The dystrophin glycoprotein complex, which connects the cell membrane to the basement membrane, is essential for a variety of biological events, including maintenance of muscle integrity. An O-mannose-type GalNAc-β3-GlcNAc-β4-Man（-6-phosphate）（core M3） structure of α-dystroglycan （αDG）, a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Hypo-glycosylation of αDG is linked to some types of inherited muscular dystrophy; consistent with this relationship, many disease-related mutations have been detected in genes involved in O-mannosyl glycan synthesis. Defects in protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 （POMGnT1）, a glycosyltransferase that participates in the formation of GlcNAc-β2-Man glycan, are causally related to muscle-eye-brain disease （MEB）, a congenital muscular dystrophy, although the role of POMGnT1 in post-phosphoryl modification of core M3 glycan remains elusive. We found that N-terminal domain of POMGnT1 （called stem domain） recognizes the β-linked GlcNAc of O-mannosyl glycan, an enzymatic product of POMGnT1. This interaction may recruit POMGnT1 to a specific site of α-DG to promote GlcNAc-β2-Man （core M1） clustering and also may recruit other enzymes that interact with POMGnT1, e.g., FKTN which is required for ribitol-phosphate modification of the core M3 glycan that is the first step of post-phosphoryl modification of core M3 glycan. These findings explain how POMGnT1 attaches GlcNAc-β to clustered O-mannose sites and influences post-phosphoryl modification of core M3. Our study provides important insight into how disease-associated mutations cause inherited muscular dystrophy pathogenesis.