Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V

Masamichi Nagae (), Yasuhiko Kizuka, Emiko Mihara, Yu Kitago, Shinya Hanashima, Yukishige Ito, Junichi Takagi, Naoyuki Taniguchi and Yoshiki Yamaguchi
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Masamichi Nagae: RIKEN
Yasuhiko Kizuka: RIKEN
Emiko Mihara: Osaka University
Yu Kitago: Osaka University
Shinya Hanashima: Osaka University
Yukishige Ito: RIKEN
Junichi Takagi: Osaka University
Naoyuki Taniguchi: RIKEN
Yoshiki Yamaguchi: RIKEN

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract N-acetylglucosaminyltransferase-V (GnT-V) alters the structure of specific N-glycans by modifying α1-6-linked mannose with a β1-6-linked N-acetylglucosamine branch. β1-6 branch formation on cell surface receptors accelerates cancer metastasis, making GnT-V a promising target for drug development. However, the molecular basis of GnT-V’s catalytic mechanism and substrate specificity are not fully understood. Here, we report crystal structures of human GnT-V luminal domain with a substrate analog. GnT-V luminal domain is composed of a GT-B fold and two accessary domains. Interestingly, two aromatic rings sandwich the α1-6 branch of the acceptor N-glycan and restrain the global conformation, partly explaining the fine branch specificity of GnT-V. In addition, interaction of the substrate N-glycoprotein with GnT-V likely contributes to protein-selective and site-specific glycan modification. In summary, the acceptor-GnT-V complex structure suggests a catalytic mechanism, explains the previously observed inhibition of GnT-V by branching enzyme GnT-III, and provides a basis for the rational design of drugs targeting N-glycan branching.

Date: 2018
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DOI: 10.1038/s41467-018-05931-w

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