Structure-function relationships of glycosyltransferases involved in muscular dystrophy disease.

• Project/Area Number: 26840029
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Structural biochemistry
• Research Institution: High Energy Accelerator Research Organization
• Principal Investigator: Kuwabara Naoyuki 大学共同利用機関法人高エネルギー加速器研究機構, 物質構造科学研究所, 研究員 (70506253)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 糖転移酵素 / ジストログリカン / 糖鎖修飾 / 筋ジストロフィー / O-マンノシル化 / αジストログリカン

Outline of Final Research Achievements

A O-mannose type GalNAc-b1,3-GlcNAc-b1,4-(phosphate-6)-Man (core M3) structure of a-dystroglycan (aDG), a subunit of the complex that is anchored to the cell membrane, directly interacts with laminin. Defects in POMGnT1, a glycosyltransferase that participates in formation of GlcNAc-b1,2-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 the stem domain of POMGnT1 recognizes the b-linked GlcNAc of O-mannose glycan. This recognition may also recruit other enzymes that interact with POMGnT1, which is required for further modification of the core M3 glycan. On the basis of our findings, we propose a mechanism for the deficiency in the post-phosphoryl modification of the glycan observed in POMGnT1 KO mice and MEB patients.

Research Products

• [Journal Article] A conserved island of BAG6/Scythe is related to ubiquitin domains and participates in short hydrophobicity recognition. (2016)
  • Author(s): Tanaka, H., Takahashi, T., Xie, Y., Minami, R., Yanagi, Y., Hayashishita, M., Suzuki, R., Yokota, N., Shimada, M., Mizushima, T., Kuwabara, N., Kato, R., Kawahara, H.
  • Journal Title: FEBS J. Volume: 283 Issue: 4 Pages: 662-677
  • DOI: 10.1111/febs.13618
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel helical assembly in arginine methyltransferase 8 (2016)
  • Author(s): Toma-Fukai S, Kim JD, Park KE, Kuwabara N, Shimizu N, Krayukhina E, Uchiyama S, Fukamizu A, Shimizu T
  • Journal Title: Journal of Molecular Biology Volume: 428 Issue: 6 Pages: 1197-1208
  • DOI: 10.1016/j.jmb.2016.02.007
  • Peer Reviewed / Open Access
• [Journal Article] POMGNT1 Is Glycosylated by Mucin-Type <i>O</i>-Glycans (2015)
  • Author(s): Xin X, Akasaka-Manya K, Manya H, Furukawa J, Kuwahara N, Okada K, Tsumoto H, Higashi N, Kato R, Shinohara Y, Irimura T, Endo T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 38 Issue: 9 Pages: 1389-1394
  • DOI: 10.1248/bpb.b15-00415
  • NAID: 130005096979
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structure of a BAG6 (Bcl-2-associated Athanogene 6)-Ubl4a (Ubiquitin-like Protein 4a) Complex Reveals a Novel Binding Interface That Functions in Tail-anchored Protein Biogenesis. (2015)
  • Author(s): Kuwabara N, Minami R, Yokota N, Matsumoto H, Senda T, Kawahara H, Kato R.
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 15 Pages: 9387-9398
  • DOI: 10.1074/jbc.m114.631804
  • Peer Reviewed / Open Access
• [Presentation] A novel carbohydrate binding domain of the POMGnT1 stem region modulates O-mannosylation sites of α-dystroglycan (2016)
  • Author(s): N Kuwabara, H Manya, T Yamada, H Tateno, Y Hirose, M Mizuno, M Ikeguchi, J Hirabayashi, T Senda, T Endo, R Kato
  • Organizer: GlycoT2016
  • Place of Presentation: トロント(カナダ）
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] 糖転移酵素POMGnT1のステムドメインは糖鎖を認識し、O-Man型修飾部位の制御を行う。 (2016)
  • Author(s): 桑原直之、萬谷博、山田健之、舘野浩章、平林淳、千田俊哉、遠藤玉夫、加藤龍一
  • Organizer: 第16回日本蛋白質科学会年会
  • Place of Presentation: 福岡国際会議場(福岡県福岡市)
  • Year and Date: 2016-06-09
• [Presentation] Presentation title：A novel carbohydrate binding domain of POMGnT1 stem region modulates O-mannosylation sites of &#61537;-dystroglycan (2016)
  • Author(s): N Kuwabara, H Manya, T Yamada, H Tateno, Y Hirose, M Mizuno, M Ikeguchi, J Hirabayashi, T Senda, T Endo, R Kato
  • Organizer: The 3rd International Symposium on Glyco-Neuroscience
  • Place of Presentation: 淡路夢舞台 (兵庫県淡路市）
  • Year and Date: 2016-01-14
  • Int'l Joint Research
• [Presentation] 糖転移酵素POMGnT1の糖鎖認識機構解析 (2015)
  • Author(s): 桑原直之、萬谷博、山田健之、舘野浩章、平林淳、千田俊哉、遠藤玉夫、加藤龍一
  • Organizer: BMB2015 (第38会日本分子生物学会年会、第88回日本生化学大会合同大会)
  • Place of Presentation: 神戸ポートアイランド(兵庫県神戸市)
  • Year and Date: 2015-12-01
• [Presentation] 糖鎖修飾酵素POMGnT1ステムドメインの機能同定と糖鎖認識機構解析 (2014)
  • Author(s): 桑原直之、萬谷博、舘野浩章、千田俊哉、平林淳、遠藤玉夫、加藤龍一
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-27