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

Cell Chem Biol. 2018 May 17;25(5):513-518.e4. doi: 10.1016/j.chembiol.2018.03.004. Epub 2018 Mar 29.


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; crystallography; intellectual disability; molecular dynamics simulations; tandem repeat proteins; tetratricopeptide repeats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Intellectual Disability / genetics*
  • Models, Molecular
  • N-Acetylglucosaminyltransferases / chemistry*
  • N-Acetylglucosaminyltransferases / genetics*
  • Point Mutation
  • Protein Conformation, alpha-Helical
  • Protein Denaturation
  • Protein Stability
  • Tetratricopeptide Repeat


  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase