POMGnT1の構造解析による筋ジストロフィー疾患発症機序解明  [in Japanese] Mechanism for the Deficiency in Post-Phosphoryl Modification of α-Dystroglycan Observed in POMGnT1-Caused Muscular Dystrophy  [in Japanese]

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Author(s)

    • 桑原 直之 KUWABARA Naoyuki
    • 高エネルギー加速器研究機構・物質構造科学研究所・構造生物学研究センター Structural Biology Research Center, Photon Factory, Institute of Material Structure Science, High Energy Accelerator Research Organization(KEK)
    • 加藤 龍一 KATO Ryuichi
    • 高エネルギー加速器研究機構・物質構造科学研究所・構造生物学研究センター Structural Biology Research Center, Photon Factory, Institute of Material Structure Science, High Energy Accelerator Research Organization(KEK)

Abstract

<p>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 <i>O</i>-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 <i>O</i>-mannosyl glycan synthesis. Defects in protein <i>O</i>-linked mannose β1,2-<i>N</i>-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 <i>O</i>-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, <i>e.g</i>., 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 <i>O</i>-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.</p>

Journal

  • Nihon Kessho Gakkaishi

    Nihon Kessho Gakkaishi 59(2-3), 114-120, 2017

    The Crystallographic Society of Japan

Codes

  • NII Article ID (NAID)
    130006767785
  • NII NACSIS-CAT ID (NCID)
    AN00188364
  • Text Lang
    JPN
  • ISSN
    0369-4585
  • NDL Article ID
    028375653
  • NDL Call No.
    Z15-138
  • Data Source
    NDL  J-STAGE 
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