Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of alpha-dystroglycan

Kuwabara Naoyuki; Manya Hiroshi; Yamada TakeyukiTateno HiroakiKanagawa MotoiKobayashi KazuhiroAkasaka-Manya KeikoHirose YurikoMizuno MamoruIkeguchi MitsunoriToda TatsushiHirabayashi JunSenda ToshiyaEndo TamaoKato Ryuichi

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Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of alpha-dystroglycan

机译：Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of alpha-dystroglycan

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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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《Proceedings of the National Academy of Sciences of the United States of America.》 |2016年第33期|9280-9285|共6页
作者
Kuwabara Naoyuki; Manya Hiroshi; Yamada TakeyukiTateno HiroakiKanagawa MotoiKobayashi KazuhiroAkasaka-Manya KeikoHirose YurikoMizuno MamoruIkeguchi MitsunoriToda TatsushiHirabayashi JunSenda ToshiyaEndo TamaoKato Ryuichi;
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作者单位

Natl Inst Adv Ind Sci & Technol, Biotechnol Res Inst Drug Discovery, Tsukuba, Ibaraki 3058568, Japan;

Kobe Univ, Grad Sch Med, Div Neurol Mol Brain Sci, Kobe, Hyogo 6500017, Japan;

Tokyo Metropolitan Geriatr Hosp, Tokyo 1730015, JapanNoguchi Inst, Lab Glycoorgan Chem, Itabashi Ku, Tokyo 1730003, JapanYokohama City Univ, Grad Sch Med Life Sci, Yokohama, Kanagawa 2300045, JapanHigh Energy Accelerator Res Org, Inst Mat Struct Sci, Struct Biol Res Ctr, Photon Factory, Tsukuba, Ibaraki 3050801, Japan;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
alpha-dystroglycanopathy; muscular dystrophy; glycosyltransferase; lectin; O-mannosyl glycan;

Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of alpha-dystroglycan

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