Recognition of a glycosylation substrate by the O-GlcNAc transferase TPR repeats

Karim Rafie; Olawale Raimi; Andrew T. Ferenbach; Vladimir S. Borodkin; Vaibhav Kapuria; Daan M. F. van Aalten

doi:10.1098/rsob.170078

Recognition of a glycosylation substrate by the O-GlcNAc transferase TPR repeats

Karim Rafie, Olawale Raimi, Andrew T. Ferenbach, Vladimir S. Borodkin, Vaibhav Kapuria, Daan M. F. van Aalten (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

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Abstract

O-linked N-acetylglucosamine (O-GlcNAc) is an essential and dynamic post-translational modification found on hundreds of nucleocytoplasmic proteins in metazoa. Although a single enzyme, O-GlcNAc transferase (OGT), generates the entire cytosolic O-GlcNAc proteome, it is not understood how it recognises its protein substrates, targeting only a fraction of serines/threonines in the metazoan proteome for glycosylation. We describe a trapped complex of human OGT with the C-terminal domain of TAB1, a key innate immunity signalling O-GlcNAc protein, revealing extensive interactions with the tetratricopeptide repeats of OGT. Confirmed by mutagenesis, this interaction suggests that glycosylation substrate specificity is achieved by recognition of a degenerate sequon in the active site combined with an extended conformation C-terminal of the O-GlcNAc target site.

Original language	English
Article number	70078
Pages (from-to)	1-9
Number of pages	9
Journal	Open Biology
Volume	7
DOIs	https://doi.org/10.1098/rsob.170078
Publication status	Published - 28 Jun 2017

Keywords

Glycosylation
Signalling
O-GlcNAc
O-GlcNAc transferase
Substrate recognition

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10.1098/rsob.170078Licence: CC BY

Final Published Version
© 2017 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
Final published version, 794 KBLicence: CC BY

Molecular Mechanisms of O-GICNAC Signalling (Investigator award)
van Aalten, D. (Investigator)
1/03/16 → 28/02/22
Project: Research

Developing O-GlcNAc transferase inhibitors - insights from substrate recognition
Rafie, K. (Author), van Aalten, D. (Supervisor), 2017
Student thesis: Doctoral Thesis › Doctor of Philosophy

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van Aalten, Daan
- Molecular Cell and Developmental Biology - Professor of Biological Chemistry
Person: Academic

Cite this

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title = "Recognition of a glycosylation substrate by the O-GlcNAc transferase TPR repeats",

abstract = "O-linked N-acetylglucosamine (O-GlcNAc) is an essential and dynamic post-translational modification found on hundreds of nucleocytoplasmic proteins in metazoa. Although a single enzyme, O-GlcNAc transferase (OGT), generates the entire cytosolic O-GlcNAc proteome, it is not understood how it recognises its protein substrates, targeting only a fraction of serines/threonines in the metazoan proteome for glycosylation. We describe a trapped complex of human OGT with the C-terminal domain of TAB1, a key innate immunity signalling O-GlcNAc protein, revealing extensive interactions with the tetratricopeptide repeats of OGT. Confirmed by mutagenesis, this interaction suggests that glycosylation substrate specificity is achieved by recognition of a degenerate sequon in the active site combined with an extended conformation C-terminal of the O-GlcNAc target site. ",

keywords = "Glycosylation, Signalling, O-GlcNAc, O-GlcNAc transferase, Substrate recognition",

author = "Karim Rafie and Olawale Raimi and Ferenbach, {Andrew T.} and Borodkin, {Vladimir S.} and Vaibhav Kapuria and {van Aalten}, {Daan M. F.}",

note = "We thank the European Synchrotron Radiation Facility (ESRF) for beam time on beam line ID29 and assistance. KR is funded by a BBSRC Studentship (1416998). This work was funded by a Wellcome Investigator Award (110061) to DMFvA. We thank Winship Herr for useful discussions. ",

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month = jun,

day = "28",

doi = "10.1098/rsob.170078",

language = "English",

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journal = "Open Biology",

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TY - JOUR

T1 - Recognition of a glycosylation substrate by the O-GlcNAc transferase TPR repeats

AU - Rafie, Karim

AU - Raimi, Olawale

AU - Ferenbach, Andrew T.

AU - Borodkin, Vladimir S.

AU - Kapuria, Vaibhav

AU - van Aalten, Daan M. F.

N1 - We thank the European Synchrotron Radiation Facility (ESRF) for beam time on beam line ID29 and assistance. KR is funded by a BBSRC Studentship (1416998). This work was funded by a Wellcome Investigator Award (110061) to DMFvA. We thank Winship Herr for useful discussions.

PY - 2017/6/28

Y1 - 2017/6/28

N2 - O-linked N-acetylglucosamine (O-GlcNAc) is an essential and dynamic post-translational modification found on hundreds of nucleocytoplasmic proteins in metazoa. Although a single enzyme, O-GlcNAc transferase (OGT), generates the entire cytosolic O-GlcNAc proteome, it is not understood how it recognises its protein substrates, targeting only a fraction of serines/threonines in the metazoan proteome for glycosylation. We describe a trapped complex of human OGT with the C-terminal domain of TAB1, a key innate immunity signalling O-GlcNAc protein, revealing extensive interactions with the tetratricopeptide repeats of OGT. Confirmed by mutagenesis, this interaction suggests that glycosylation substrate specificity is achieved by recognition of a degenerate sequon in the active site combined with an extended conformation C-terminal of the O-GlcNAc target site.

AB - O-linked N-acetylglucosamine (O-GlcNAc) is an essential and dynamic post-translational modification found on hundreds of nucleocytoplasmic proteins in metazoa. Although a single enzyme, O-GlcNAc transferase (OGT), generates the entire cytosolic O-GlcNAc proteome, it is not understood how it recognises its protein substrates, targeting only a fraction of serines/threonines in the metazoan proteome for glycosylation. We describe a trapped complex of human OGT with the C-terminal domain of TAB1, a key innate immunity signalling O-GlcNAc protein, revealing extensive interactions with the tetratricopeptide repeats of OGT. Confirmed by mutagenesis, this interaction suggests that glycosylation substrate specificity is achieved by recognition of a degenerate sequon in the active site combined with an extended conformation C-terminal of the O-GlcNAc target site.

KW - Glycosylation

KW - Signalling

KW - O-GlcNAc

KW - O-GlcNAc transferase

KW - Substrate recognition

U2 - 10.1098/rsob.170078

DO - 10.1098/rsob.170078

M3 - Article

C2 - 28659383

SN - 2046-2441

VL - 7

SP - 1

EP - 9

JO - Open Biology

JF - Open Biology

M1 - 70078

ER -

Recognition of a glycosylation substrate by the O-GlcNAc transferase TPR repeats

Abstract

Keywords

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Projects

Molecular Mechanisms of O-GICNAC Signalling (Investigator award)

Student theses

Developing O-GlcNAc transferase inhibitors - insights from substrate recognition

Profiles

van Aalten, Daan

Cite this