The O-GlcNAc Transferase Intellectual Disability Mutation L254F Distorts the TPR Helix

Mehmet Gundogdu; Salome Llabres; Andrii Gorelik; Andrew Ferenbach; Ulrich Zachariae; Daan Van Aalten

doi:10.1016/j.chembiol.2018.03.004

The O-GlcNAc Transferase Intellectual Disability Mutation L254F Distorts the TPR Helix

Mehmet Gundogdu, Salome Llabres, Andrii Gorelik, Andrew Ferenbach, Ulrich Zachariae, Daan Van Aalten (Lead / Corresponding author)

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

28 Citations (Scopus)

207 Downloads (Pure)

Abstract

O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential post-translational modification that is abundant in the brain. Recently, OGT mutations have been associated with intellectual disability, although it is not understood how they affect OGT structure and function. Using a multi-disciplinary approach we show that the L254F OGT mutation leads to conformational changes of the tetratricopeptide repeats and reduced activity, revealing the molecular mechanisms contributing to pathogenesis.

Original language	English
Pages (from-to)	513-518.e4
Number of pages	10
Journal	Cell Chemical Biology
Volume	25
Issue number	5
Early online date	29 Mar 2018
DOIs	https://doi.org/10.1016/j.chembiol.2018.03.004
Publication status	Published - 17 May 2018

Keywords

O-GlcNAc transferase
intellectual disability
tandem repeat proteins
tetratricopeptide repeats
molecular dynamics simulations
crystallography

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmacology

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10.1016/j.chembiol.2018.03.004Licence: CC BY

Final Published VersionFinal published version, 1.66 MBLicence: CC BY

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

Genetic encoding of a stable O-GlcNAc analogue
Gorelik, A. (Author), van Aalten, D. (Supervisor), 2018
Student thesis: Doctoral Thesis › Doctor of Philosophy

File

Zachariae, Ulrich
- Biological Chemistry and Drug Discovery - Professor of Molecular Biophysics
Person: Academic

Cite this

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title = "The O-GlcNAc Transferase Intellectual Disability Mutation L254F Distorts the TPR Helix",

abstract = "O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential post-translational modification that is abundant in the brain. Recently, OGT mutations have been associated with intellectual disability, although it is not understood how they affect OGT structure and function. Using a multi-disciplinary approach we show that the L254F OGT mutation leads to conformational changes of the tetratricopeptide repeats and reduced activity, revealing the molecular mechanisms contributing to pathogenesis.",

keywords = "O-GlcNAc transferase, intellectual disability, tandem repeat proteins, tetratricopeptide repeats, molecular dynamics simulations, crystallography",

author = "Mehmet Gundogdu and Salome Llabres and Andrii Gorelik and Andrew Ferenbach and Ulrich Zachariae and {Van Aalten}, Daan",

note = "This work funded by a Wellcome Trust Investigator Award (110061) to D.M.F.v.A and a Wellcome Trust ISSF award to U.Z. M.G. was supported by a University of Dundee Translational Medical Research Fund Ph.D. fellowship. AG was supported by a Wellcome Trust PhD studentship ",

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month = may,

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doi = "10.1016/j.chembiol.2018.03.004",

language = "English",

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T1 - The O-GlcNAc Transferase Intellectual Disability Mutation L254F Distorts the TPR Helix

AU - Gundogdu, Mehmet

AU - Llabres, Salome

AU - Gorelik, Andrii

AU - Ferenbach, Andrew

AU - Zachariae, Ulrich

AU - Van Aalten, Daan

N1 - This work funded by a Wellcome Trust Investigator Award (110061) to D.M.F.v.A and a Wellcome Trust ISSF award to U.Z. M.G. was supported by a University of Dundee Translational Medical Research Fund Ph.D. fellowship. AG was supported by a Wellcome Trust PhD studentship

PY - 2018/5/17

Y1 - 2018/5/17

N2 - O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential post-translational modification that is abundant in the brain. Recently, OGT mutations have been associated with intellectual disability, although it is not understood how they affect OGT structure and function. Using a multi-disciplinary approach we show that the L254F OGT mutation leads to conformational changes of the tetratricopeptide repeats and reduced activity, revealing the molecular mechanisms contributing to pathogenesis.

AB - O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential post-translational modification that is abundant in the brain. Recently, OGT mutations have been associated with intellectual disability, although it is not understood how they affect OGT structure and function. Using a multi-disciplinary approach we show that the L254F OGT mutation leads to conformational changes of the tetratricopeptide repeats and reduced activity, revealing the molecular mechanisms contributing to pathogenesis.

KW - O-GlcNAc transferase

KW - intellectual disability

KW - tandem repeat proteins

KW - tetratricopeptide repeats

KW - molecular dynamics simulations

KW - crystallography

U2 - 10.1016/j.chembiol.2018.03.004

DO - 10.1016/j.chembiol.2018.03.004

M3 - Article

C2 - 29606577

SN - 2451-9456

VL - 25

SP - 513-518.e4

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 5

ER -

The O-GlcNAc Transferase Intellectual Disability Mutation L254F Distorts the TPR Helix

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

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Projects

Molecular Mechanisms of O-GICNAC Signalling (Investigator award)

Student theses

Genetic encoding of a stable O-GlcNAc analogue

Profiles

Zachariae, Ulrich

Cite this