The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases

  • Nat Chem Biol. 2018 Jul;14(7):688-695. doi: 10.1038/s41589-018-0071-y.
Suzana Markolovic  1 ,  Qinqin Zhuang  2 ,  Sarah E Wilkins  1 ,  Charlotte D Eaton  2 ,  Martine I Abboud  1 ,  Maximiliano J Katz  3 ,  Helen E McNeil  2 ,  Robert K Leśniak  1 ,  Charlotte Hall  2 ,  Weston B Struwe  1 ,  Rebecca Konietzny  4 ,  Simon Davis  4 ,  Ming Yang  4  5 ,  Wei Ge  1 ,  Justin L P Benesch  1 ,  Benedikt M Kessler  4 ,  Peter J Ratcliffe  4  5 ,  Matthew E Cockman  4  5 ,  Roman Fischer  4 ,  Pablo Wappner  3 ,  Rasheduzzaman Chowdhury  6  7 ,  Mathew L Coleman  8 ,  Christopher J Schofield  9
Affiliations
  • 1. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
  • 2. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • 3. Instituto Leloir, Buenos Aires, Argentina.
  • 4. Target Discovery Institute, University of Oxford, Oxford, UK.
  • 5. The Francis Crick Institute, London, UK.
  • 6. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK. [email protected].
  • 7. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Clark Center, Stanford, CA, USA. [email protected].
  • 8. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. [email protected].
  • 9. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK. [email protected].
PMID: 29915238 DOI: 10.1038/s41589-018-0071-y
Abstract

Biochemical, structural and cellular studies reveal Jumonji-C (JmjC) domain-containing 7 (JMJD7) to be a 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes (3S)-lysyl hydroxylation. Crystallographic analyses reveal JMJD7 to be more closely related to the JmjC hydroxylases than to the JmjC demethylases. Biophysical and mutation studies show that JMJD7 has a unique dimerization mode, with interactions between monomers involving both N- and C-terminal regions and disulfide bond formation. A proteomic approach identifies two related members of the translation factor (TRAFAC) family of GTPases, developmentally regulated GTP-binding proteins 1 and 2 (DRG1/2), as activity-dependent JMJD7 interactors. Mass spectrometric analyses demonstrate that JMJD7 catalyzes Fe(II)- and 2OG-dependent hydroxylation of a highly conserved lysine residue in DRG1/2; amino-acid analyses reveal that JMJD7 catalyzes (3S)-lysyl hydroxylation. The functional assignment of JMJD7 will enable future studies to define the role of DRG hydroxylation in cell growth and disease.