Carbohydrate-binding domain of the POMGnT1 stem region modulates O -mannosylation sites of α-dystroglycan
- 4 August 2016
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 113 (33), 9280-9285
- https://doi.org/10.1073/pnas.1525545113
Abstract
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-β1,3-GlcNAc-β1,4-(phosphate-6)-Man structure of α-dystroglycan (α-DG), a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Reduced glycosylation of α-DG 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-β1,2-Man glycan, are causally related to muscle-eye-brain disease (MEB), a congenital muscular dystrophy, although the role of POMGnT1 in postphosphoryl modification of GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man glycan remains elusive. Our crystal structures of POMGnT1 agreed with our previous results showing that the catalytic domain recognizes substrate O-mannosylated proteins via hydrophobic interactions with little sequence specificity. Unexpectedly, we found that the 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-β1,2-Man clustering and also may recruit other enzymes that interact with POMGnT1, e.g., fukutin, which is required for further modification of the GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man glycan. On the basis of our findings, we propose a mechanism for the deficiency in postphosphoryl modification of the glycan observed in POMGnT1-KO mice and MEB patients.Keywords
Funding Information
- Japan Society for the Promotion of Science (Young Scientists (B) 26840029)
- Japan Society for the Promotion of Science (Young Scientists (B) 26860682)
- Japan Society for the Promotion of Science (Scientific Research (B) 25293016)
- Japan Society for the Promotion of Science (Scientific Research (C) 16K07284)
- Japan Society for the Promotion of Science (Scientific Research (B) 20370053)
- Japan Society for the Promotion of Science (Scientific Research on Innovative Areas 26110727)
- Mizutani Foundation (Glycoscience 150171)
- NCNP (Intramural Research Grant 26-8 for Neurological and Psychiatric Disorders)
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