Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 33, Pages 9280-9285Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1525545113
Keywords
alpha-dystroglycanopathy; muscular dystrophy; glycosyltransferase; lectin; O-mannosyl glycan
Categories
Funding
- Ministry of Education, Sports, Science and Technology of Japan
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science [JP26840029, JP26860682, JP25293016, JP16K07284, JP20370053]
- Scientific Research on Innovative Areas Grant [26110727]
- Mizutani Foundation for Glycoscience [150171]
- Japan National Center Hospital for Neurological and Psychiatric Disorders [26-8]
- Grants-in-Aid for Scientific Research [26110727, 26253057, 15H04352, 16K08262, 16H05071, 16K18522, 16H05353] Funding Source: KAKEN
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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-beta 1,3-GlcNAc-beta 1,4-(phosphate-6)-Man structure of alpha-dystroglycan (alpha-DG), a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Reduced glycosylation of alpha-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 beta 1,2-N-acetylglucosaminyltransferase 1 (POMGnT1), a glycosyltransferase that participates in the formation of GlcNAc-beta 1,2-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-beta 1,3-GlcNAc-beta 1,4-(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 beta-linked GlcNAc of O-mannosyl glycan, an enzymatic product of POMGnT1. This interaction may recruit POMGnT1 to a specific site of alpha-DG to promote GlcNAc-beta 1,2-Man clustering and also may recruit other enzymes that interact with POMGnT1, e.g., fukutin, which is required for further modification of the GalNAc-beta 1,3-GlcNAc-beta 1,4-(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.
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