skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase

Abstract

The O-linked β-N-acetyl glucosamine (O-GlcNAc) modification dynamically regulates the functions of numerous proteins. A single human enzyme O-linked β-N-acetyl glucosaminase (O-GlcNAcase or OGA) hydrolyzes this modification. To date, it remains largely unknown how OGA recognizes various substrates. Here we report the structures of OGA in complex with each of four distinct glycopeptide substrates that contain a single O-GlcNAc modification on a serine or threonine residue. Intriguingly, these glycopeptides bind in a bidirectional yet conserved conformation within the substrate-binding cleft of OGA. This study provides fundamental insights into a general principle that confers the substrate binding adaptability and specificity to OGA in O-GlcNAc regulation.

Authors:
 [1]; ORCiD logo [1];  [1];  [1]
  1. Univ. of Wisconsin, Madison, WI (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1438911
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
[ Journal Volume: 8; Journal Issue: 1]; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Glycobiology; X-ray crystallography

Citation Formats

Li, Baobin, Li, Hao, Hu, Chia-Wei, and Jiang, Jiaoyang. Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase. United States: N. p., 2017. Web. doi:10.1038/s41467-017-00865-1.
Li, Baobin, Li, Hao, Hu, Chia-Wei, & Jiang, Jiaoyang. Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase. United States. doi:10.1038/s41467-017-00865-1.
Li, Baobin, Li, Hao, Hu, Chia-Wei, and Jiang, Jiaoyang. Fri . "Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase". United States. doi:10.1038/s41467-017-00865-1. https://www.osti.gov/servlets/purl/1438911.
@article{osti_1438911,
title = {Structural insights into the substrate binding adaptability and specificity of human O-GlcNAcase},
author = {Li, Baobin and Li, Hao and Hu, Chia-Wei and Jiang, Jiaoyang},
abstractNote = {The O-linked β-N-acetyl glucosamine (O-GlcNAc) modification dynamically regulates the functions of numerous proteins. A single human enzyme O-linked β-N-acetyl glucosaminase (O-GlcNAcase or OGA) hydrolyzes this modification. To date, it remains largely unknown how OGA recognizes various substrates. Here we report the structures of OGA in complex with each of four distinct glycopeptide substrates that contain a single O-GlcNAc modification on a serine or threonine residue. Intriguingly, these glycopeptides bind in a bidirectional yet conserved conformation within the substrate-binding cleft of OGA. This study provides fundamental insights into a general principle that confers the substrate binding adaptability and specificity to OGA in O-GlcNAc regulation.},
doi = {10.1038/s41467-017-00865-1},
journal = {Nature Communications},
number = [1],
volume = [8],
place = {United States},
year = {2017},
month = {9}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 6 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Structures of human O-GlcNAcase and its complexes reveal a new substrate recognition mode
journal, March 2017

  • Li, Baobin; Li, Hao; Lu, Lei
  • Nature Structural & Molecular Biology, Vol. 24, Issue 4
  • DOI: 10.1038/nsmb.3390

Refinement of Macromolecular Structures by the Maximum-Likelihood Method
journal, May 1997

  • Murshudov, G. N.; Vagin, A. A.; Dodson, E. J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3
  • DOI: 10.1107/S0907444996012255

Structure and mechanism of a bacterial β-glucosaminidase having O-GlcNAcase activity
journal, March 2006

  • Dennis, Rebecca J.; Taylor, Edward J.; Macauley, Matthew S.
  • Nature Structural & Molecular Biology, Vol. 13, Issue 4
  • DOI: 10.1038/nsmb1079

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

Structural insights into the mechanism and inhibition of eukaryotic O-GlcNAc hydrolysis
journal, March 2006

  • Rao, Francesco V.; Dorfmueller, Helge C.; Villa, Fabrizio
  • The EMBO Journal, Vol. 25, Issue 7
  • DOI: 10.1038/sj.emboj.7601026

Human OGA binds substrates in a conserved peptide recognition groove
journal, October 2010

  • Schimpl, Marianne; Schüttelkopf, Alexander W.; Borodkin, Vladimir S.
  • Biochemical Journal, Vol. 432, Issue 1
  • DOI: 10.1042/BJ20101338

Structural snapshots of the reaction coordinate for O-GlcNAc transferase
journal, October 2012

  • Lazarus, Michael B.; Jiang, Jiaoyang; Gloster, Tracey M.
  • Nature Chemical Biology, Vol. 8, Issue 12
  • DOI: 10.1038/nchembio.1109

Dynamic O -Glycosylation of Nuclear and Cytosolic Proteins : CLONING AND CHARACTERIZATION OF A NEUTRAL, CYTOSOLIC β-
journal, January 2001

  • Gao, Yuan; Wells, Lance; Comer, Frank I.
  • Journal of Biological Chemistry, Vol. 276, Issue 13
  • DOI: 10.1074/jbc.M010420200

A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo
journal, June 2008

  • Yuzwa, Scott A.; Macauley, Matthew S.; Heinonen, Julia E.
  • Nature Chemical Biology, Vol. 4, Issue 8
  • DOI: 10.1038/nchembio.96

Analysis of PUGNAc and NAG-thiazoline as Transition State Analogues for Human O -GlcNAcase:  Mechanistic and Structural Insights into Inhibitor Selectivity and Transition State Poise
journal, January 2007

  • Whitworth, Garrett E.; Macauley, Matthew S.; Stubbs, Keith A.
  • Journal of the American Chemical Society, Vol. 129, Issue 3
  • DOI: 10.1021/ja065697o

The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin α
journal, September 2004

  • Jínek, Martin; Rehwinkel, Jan; Lazarus, Brooke D.
  • Nature Structural & Molecular Biology, Vol. 11, Issue 10
  • DOI: 10.1038/nsmb833

Visualizing the Reaction Coordinate of an O-GlcNAc Hydrolase
journal, February 2010

  • He, Yuan; Macauley, Matthew S.; Stubbs, Keith A.
  • Journal of the American Chemical Society, Vol. 132, Issue 6
  • DOI: 10.1021/ja9086769

Dynamic Glycosylation of Nuclear and Cytosolic Proteins: CLONING AND CHARACTERIZATION OF A UNIQUE
journal, April 1997

  • Kreppel, Lisa K.; Blomberg, Melissa A.; Hart, Gerald W.
  • Journal of Biological Chemistry, Vol. 272, Issue 14
  • DOI: 10.1074/jbc.272.14.9308

Structure of human O-GlcNAc transferase and its complex with a peptide substrate
journal, January 2011

  • Lazarus, Michael B.; Nam, Yunsun; Jiang, Jiaoyang
  • Nature, Vol. 469, Issue 7331
  • DOI: 10.1038/nature09638

The active site of O-GlcNAc transferase imposes constraints on substrate sequence
journal, August 2015

  • Pathak, Shalini; Alonso, Jana; Schimpl, Marianne
  • Nature Structural & Molecular Biology, Vol. 22, Issue 9
  • DOI: 10.1038/nsmb.3063

Protein O-GlcNAcylation: emerging mechanisms and functions
journal, May 2017

  • Yang, Xiaoyong; Qian, Kevin
  • Nature Reviews Molecular Cell Biology, Vol. 18, Issue 7
  • DOI: 10.1038/nrm.2017.22

PHENIX : building new software for automated crystallographic structure determination
journal, October 2002

  • Adams, Paul D.; Grosse-Kunstleve, Ralf W.; Hung, Li-Wei
  • Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 11
  • DOI: 10.1107/S0907444902016657

Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins
journal, April 2007

  • Hart, Gerald W.; Housley, Michael P.; Slawson, Chad
  • Nature, Vol. 446, Issue 7139
  • DOI: 10.1038/nature05815

O -GlcNAcase Uses Substrate-assisted Catalysis : KINETIC ANALYSIS AND DEVELOPMENT OF HIGHLY SELECTIVE MECHANISM-INSPIRED INHIBITORS
journal, March 2005

  • Macauley, Matthew S.; Whitworth, Garrett E.; Debowski, Aleksandra W.
  • Journal of Biological Chemistry, Vol. 280, Issue 27
  • DOI: 10.1074/jbc.M413819200

Structural and functional insight into human O-GlcNAcase
journal, March 2017

  • Roth, Christian; Chan, Sherry; Offen, Wendy A.
  • Nature Chemical Biology, Vol. 13, Issue 6
  • DOI: 10.1038/nchembio.2358

Insights into activity and inhibition from the crystal structure of human O-GlcNAcase
journal, March 2017

  • Elsen, Nathaniel L.; Patel, Sangita B.; Ford, Rachael E.
  • Nature Chemical Biology, Vol. 13, Issue 6
  • DOI: 10.1038/nchembio.2357

O -GlcNAcase: Promiscuous Hexosaminidase or Key Regulator of O -GlcNAc Signaling?
journal, October 2014

  • Alonso, Jana; Schimpl, Marianne; van Aalten, Daan M. F.
  • Journal of Biological Chemistry, Vol. 289, Issue 50
  • DOI: 10.1074/jbc.R114.609198

O -Linked GlcNAc Transferase Is a Conserved Nucleocytoplasmic Protein Containing Tetratricopeptide Repeats
journal, April 1997

  • Lubas, William A.; Frank, David W.; Krause, Michael
  • Journal of Biological Chemistry, Vol. 272, Issue 14
  • DOI: 10.1074/jbc.272.14.9316

A Novel Quantitative Mass Spectrometry Platform for Determining Protein O-GlcNAcylation Dynamics
journal, April 2016

  • Wang, Xiaoshi; Yuan, Zuo-Fei; Fan, Jing
  • Molecular & Cellular Proteomics, Vol. 15, Issue 7
  • DOI: 10.1074/mcp.O115.049627

Evidence for a Functional O -Linked N -Acetylglucosamine ( O -GlcNAc) System in the Thermophilic Bacterium Thermobaculum terrenum
journal, October 2015

  • Ostrowski, Adam; Gundogdu, Mehmet; Ferenbach, Andrew T.
  • Journal of Biological Chemistry, Vol. 290, Issue 51
  • DOI: 10.1074/jbc.M115.689596

Synergy of Peptide and Sugar in O-GlcNAcase Substrate Recognition
journal, February 2012