5GGF

Crystal structure of human protein O-mannose beta-1,2-N-acetylglucosaminyltransferase form II

Summary for 5GGF

• Entry DOI: 10.2210/pdb5ggf/pdb
• Related: 5GGG 5GGI 5GGJ 5GGK 5GGL 5GGN 5GGO 5GGP
• Descriptor: Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (2 entities in total)
• Functional Keywords: glycosyltransferase, o-mannosylation, alpha-dystroglycan, transferase, sugar binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 196654.36

Authors

Kuwabara, N.,Senda, T.,Kato, R. (deposition date: 2016-06-15, release date: 2016-08-10, Last modification date: 2020-02-26)

Primary citation

Kuwabara, N.,Manya, H.,Yamada, T.,Tateno, H.,Kanagawa, M.,Kobayashi, K.,Akasaka-Manya, K.,Hirose, Y.,Mizuno, M.,Ikeguchi, M.,Toda, T.,Hirabayashi, J.,Senda, T.,Endo, T.,Kato, R.
Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of alpha-dystroglycan
Proc.Natl.Acad.Sci.USA, 113:9280-9285, 2016

PubMed 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.

PubMed: 27493216
DOI: 10.1073/pnas.1525545113

Experimental method

X-RAY DIFFRACTION (2.49 Å)