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

Nature Communications
Masamichi NagaeYoshiki Yamaguchi

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.

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Citations

Apr 4, 2019·FEBS Letters·Yoichiro HaradaIkuro Maruyama
Aug 21, 2019·Nature Chemical Biology·Kelley W Moremen, Robert S Haltiwanger
Oct 18, 2019·Traffic·Sadia RahmaniCostin N Antonescu
Oct 24, 2019·Current Molecular Medicine·Zsuzsanna ElekZsolt Rónai
Feb 13, 2020·European Journal of Nuclear Medicine and Molecular Imaging·Asma BashirIan Law
Jan 16, 2020·International Journal of Molecular Sciences·Masamichi NagaeYasuhiko Kizuka
Jul 1, 2020·Frontiers in Oncology·Yuli JianShujing Wang
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Jan 1, 2021·Frontiers in Cardiovascular Medicine·Alkmini A Papadopoulou, Regina Fluhrer
Oct 23, 2020·Nature Reviews. Molecular Cell Biology·Katrine T SchjoldagerHenrik Clausen
Mar 5, 2021·Biomarkers : Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals·Tijl VermassenJoris Delanghe
Mar 18, 2021·Developmental Cell·Yi-Fan HuangMorihisa Fujita
Sep 6, 2020·Biochimica Et Biophysica Acta. General Subjects·Tetsuya HirataYasuhiko Kizuka
May 2, 2021·Journal of Experimental & Clinical Cancer Research : CR·Xiaoqing SunHuanxin Lin
Aug 28, 2021·International Journal of Molecular Sciences·Yuki OhkawaNaoyuki Taniguchi
Jan 7, 2022·Journal of Biomolecular Structure & Dynamics·Michael Russelle S AlvarezGladys C Completo

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Datasets Mentioned

BETA
L08599

Methods Mentioned

BETA
NMR
glycosylation
PCR
size exclusion chromatography

Software Mentioned

XDS
SUPERPOSE
Phenix
MOLREP
GraphPad Prism
NCONT
CCP4
AIMLESS
Refmac5
Protein Complex Suite

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