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 journalArticle

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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 languageEnglish
Pages (from-to)513-518.e4
Number of pages10
JournalCell Chemical Biology
Volume25
Issue number5
Early online date29 Mar 2018
DOIs
Publication statusPublished - 17 May 2018

Fingerprint

Intellectual Disability
Mutation
Acetylglucosamine
Post Translational Protein Processing
Brain
O-GlcNAc transferase
Proteins

Keywords

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

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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The O-GlcNAc Transferase Intellectual Disability Mutation L254F Distorts the TPR Helix. / Gundogdu, Mehmet; Llabres, Salome; Gorelik, Andrii; Ferenbach, Andrew; Zachariae, Ulrich; Van Aalten, Daan (Lead / Corresponding author).

In: Cell Chemical Biology, Vol. 25, No. 5, 17.05.2018, p. 513-518.e4.

Research output: Contribution to journalArticle

TY - JOUR

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

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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.

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KW - intellectual disability

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KW - tetratricopeptide repeats

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KW - crystallography

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