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Molecular & Cellular Proteomics

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Research

Bisecting GlcNAc Is a General Suppressor of Terminal Modification of N-glycan

Miyako Nakano, View ORCID ProfileSushil K. Mishra, Yuko Tokoro, Keiko Sato, Kazuki Nakajima, Yoshiki Yamaguchi, Naoyuki Taniguchi and Yasuhiko Kizuka  Correspondence email
Molecular & Cellular Proteomics October 1, 2019, First published on August 2, 2019, 18 (10) 2044-2057; https://doi.org/10.1074/mcp.RA119.001534
Miyako Nakano
Graduate School of Advanced Sciences of Matter, Hiroshima University, 1-3-1 Kagamiyama, Higashihiroshima, Hiroshima 739-8530, Japan
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Sushil K. Mishra
Glycoscience Group, National University of Ireland, Galway, IrelandStructural Glycobiology Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
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  • ORCID record for Sushil K. Mishra
Yuko Tokoro
Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
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Keiko Sato
Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
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Kazuki Nakajima
Division of Clinical Research Promotion and Support, Center for Research Promotion, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
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Yoshiki Yamaguchi
Structural Glycobiology Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, JapanSynthetic Cellular Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
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Naoyuki Taniguchi
Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, JapanDepartment of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuoku, Osaka 541-8567, Japan
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Yasuhiko Kizuka
Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, 1-1 Yanagido, Gifu 501-1193, JapanDisease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
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  • For correspondence: kizuka@gifu-u.ac.jp
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Graphical Abstract

Figure1
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Highlights

  • Loss of bisecting GlcNAc in N-glycan increases various terminal glycan modifications.

  • Glycosyltransferases commonly do not act well on glycans with bisecting GlcNAc.

  • Presence of bisecting GlcNAc alters overall conformation of N-glycan.

  • Bisecting GlcNAc serves as a general suppressor for terminal modification.

Abstract

Glycoproteins are decorated with complex glycans for protein functions. However, regulation mechanisms of complex glycan biosynthesis are largely unclear. Here we found that bisecting GlcNAc, a branching sugar residue in N-glycan, suppresses the biosynthesis of various types of terminal epitopes in N-glycans, including fucose, sialic acid and human natural killer-1. Expression of these epitopes in N-glycan was elevated in mice lacking the biosynthetic enzyme of bisecting GlcNAc, GnT-III, and was conversely suppressed by GnT-III overexpression in cells. Many glycosyltransferases for N-glycan terminals were revealed to prefer a nonbisected N-glycan as a substrate to its bisected counterpart, whereas no up-regulation of their mRNAs was found. This indicates that the elevated expression of the terminal N-glycan epitopes in GnT-III-deficient mice is attributed to the substrate specificity of the biosynthetic enzymes. Molecular dynamics simulations further confirmed that nonbisected glycans were preferentially accepted by those glycosyltransferases. These findings unveil a new regulation mechanism of protein N-glycosylation.

  • Glycomics
  • glycoprotein pathways
  • glycosylation
  • glycoproteins
  • glycoprotein structure
  • glycoproteomics
  • bisecting GlcNAc
  • fucosylation
  • GnT-III
  • HNK-1
  • sialylation

Footnotes

  • Author contributions: M.N., S.K.M., Y.T., K.S., K.N., and Y.K. performed research; M.N., K.N., Y.Y., N.T., and Y.K. analyzed data; S.K.M., Y.Y., and Y.K. wrote the paper; Y.K. designed research; Y.K. contributed new reagents/analytic tools.

  • ↵* This work was supported by Grant-in-Aid for Scientific Research (C) to Y.K. [17K07356], Leading Initiative for Excellent Young Researchers (LEADER) project to Y.K. from the Japan Society for the Promotion of Science (JSPS), by Takeda Science Foundation, and by Mochida Memorial Foundation for Medical and Pharmaceutical Research.

  • ↵Embedded Image This article contains supplemental Figures and Tables.

  • Received April 29, 2019.
  • Revision received August 1, 2019.
  • © 2019 Nakano et al.

Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

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Bisecting GlcNAc Is a General Suppressor of Terminal Modification of N-glycan
Miyako Nakano, Sushil K. Mishra, Yuko Tokoro, Keiko Sato, Kazuki Nakajima, Yoshiki Yamaguchi, Naoyuki Taniguchi, Yasuhiko Kizuka
Molecular & Cellular Proteomics October 1, 2019, First published on August 2, 2019, 18 (10) 2044-2057; DOI: 10.1074/mcp.RA119.001534

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Bisecting GlcNAc Is a General Suppressor of Terminal Modification of N-glycan
Miyako Nakano, Sushil K. Mishra, Yuko Tokoro, Keiko Sato, Kazuki Nakajima, Yoshiki Yamaguchi, Naoyuki Taniguchi, Yasuhiko Kizuka
Molecular & Cellular Proteomics October 1, 2019, First published on August 2, 2019, 18 (10) 2044-2057; DOI: 10.1074/mcp.RA119.001534
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Molecular & Cellular Proteomics: 18 (10)
Molecular & Cellular Proteomics
Vol. 18, Issue 10
1 Oct 2019
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