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

Nature Chemical Biology volume 14, pages 688–695 (2018)Cite this article

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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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Fig. 1: Structural analyses of the JmjC hydroxylase, JMJD7.
Fig. 2: JMJD7 interacts with DRG–DFRP complexes in an active-site-dependent manner.
Fig. 3: JMJD7 catalyzes lysyl hydroxylation of the DRG1/2 GTPases.
Fig. 4: JMJD7 is a (3S)-lysyl hydroxylase that promotes DRG ribonucleic acid binding.

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  • 27 June 2018

    In the version of this article initially published, authors Sarah E. Wilkins, Charlotte D. Eaton, Martine I. Abboud and Maximiliano J. Katz were incorrectly included in the equal contributions footnote in the affiliations list. Footnote number seven linking to the equal contributions statement should be present only for Suzana Markolovic and Qinqin Zhuang, and the statement should read “These authors contributed equally: Suzana Markolovic, Qinqin Zhuang.” The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank the Biotechnology and Biological Sciences Research Council (BB/L009846/1, C.J.S.), the Medical Research Council (MR/N021053/1, M.L.C.), the Wellcome Trust (106244/Z/14/Z, C.J.S.), Cancer Research UK (24552, M.L.C.), the University of Oxford Clarendon Fund (S.M.) and Kellogg College, University of Oxford (through a Junior Research Fellowship; M.I.A.) for support. We thank E. Flashman (Department of Chemistry, University of Oxford) for assistance with the 18O2 experiment and K. Connolly (Institute of Cancer and Genomics Sciences, University of Birmingham) for Drosophila cDNA.

Author information

Author notes

  1. Rasheduzzaman Chowdhury

    Present address: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Clark Center, Stanford, CA, USA

  2. These authors contributed equally: Suzana Markolovic, Qinqin Zhuang.

  3. These authors jointly supervised this work: Mathew L. Coleman, Christopher J. Schofield.

Authors and Affiliations

  1. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK

    Suzana Markolovic, Sarah E. Wilkins, Martine I. Abboud, Robert K. Leśniak, Weston B. Struwe, Wei Ge, Justin L. P. Benesch, Rasheduzzaman Chowdhury & Christopher J. Schofield

  2. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK

    Qinqin Zhuang, Charlotte D. Eaton, Helen E. McNeil, Charlotte Hall & Mathew L. Coleman

  3. Instituto Leloir, Buenos Aires, Argentina

    Maximiliano J. Katz & Pablo Wappner

  4. Target Discovery Institute, University of Oxford, Oxford, UK

    Rebecca Konietzny, Simon Davis, Ming Yang, Benedikt M. Kessler, Peter J. Ratcliffe, Matthew E. Cockman & Roman Fischer

  5. The Francis Crick Institute, London, UK

    Ming Yang, Peter J. Ratcliffe & Matthew E. Cockman

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Contributions

The following 'second authors' contributed equally: S.E.W., C.D.E., M.I.A. and M.J.K. S.M., Q.Z., S.E.W., M.J.K., P.W., R.C., M.L.C. and C.J.S. designed and conceived the research; S.M. prepared all recombinant JMJD7 constructs and performed and analyzed CD experiments and all enzyme activity assays by MALDI-MS and NMR; Q.Z. performed substrate discovery proteomics, enzyme–substrate interaction assays, all JMJD7 loss-of-function experiments, and DRG–DFRP interaction, GTPase and RNA-binding assays; S.M. and R.C. performed the crystallography in which R.C. played both an experimental and supervisory role; C.D.E. performed confocal microscopy, cellular dimerization, and dmJMJD7 interaction experiments; Q.Z., C.H. and H.E.M. prepared mammalian expression constructs used by Q.Z.; W.G. and S.M. prepared plasmids for recombinant protein production; S.M. performed and analyzed amino-acid analyses with guidance from S.E.W.; M.I.A. performed and analyzed peptide NMR work, produced and purified recombinant DRG1, performed DRG1 stability and activity assays, and analyzed data; Q.Z. purified exogenous and endogenous proteins for MS and analyzed data with help from M.L.C.; R.K., S.D. and R.F. performed MS and analyzed data; B.M.K. provided MS instrument use. R.K.L. prepared hydroxylysine standards; S.M. and W.B.S. performed and analyzed native MS/SEC-MALS; J.L.P.B. provided SEC-MALS instrument use. M.J.K. and P.W. performed and analyzed Drosophila experiments; R.C. performed enzyme–substrate modeling, prepared recombinant dmJMJD7 and performed proteolysis assays; M.Y., M.E.C. and P.J.R. performed preliminary immunoprecipitations; S.M., Q.Z., S.E.W., C.D.E., R.C., M.L.C. and C.J.S. analyzed data; S.M., Q.Z., R.C., M.L.C. and C.J.S. wrote the manuscript.

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Correspondence to Rasheduzzaman Chowdhury, Mathew L. Coleman or Christopher J. Schofield.

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Markolovic, S., Zhuang, Q., Wilkins, S.E. et al. The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases. Nat Chem Biol 14, 688–695 (2018). https://doi.org/10.1038/s41589-018-0071-y

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