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

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

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. rashed.chowdhury@stanford.edu.
  • 7 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Clark Center, Stanford, CA, USA. rashed.chowdhury@stanford.edu.
  • 8 Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. m.coleman@bham.ac.uk.
  • 9 Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK. christopher.schofield@chem.ox.ac.uk.
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.

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