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

DOI: 10.1038/s41589-018-0071-y DOI Help

Authors: Suzana Markolovic (University of Oxford) , Qinqin Zhuang (University of Birmingham) , Sarah E. Wilkins (University of Oxford) , Charlotte D. Eaton (University of Birmingham) , Martine I. Abboud (University of Oxford) , Maximiliano J. Katz (Instituto Leloir) , Helen E. Mcneil (University of Birmingham) , Robert K. LeĊ›niak (University of Oxford) , Charlotte Hall (University of Birmingham) , Weston B. Struwe (University of Oxford) , Rebecca Konietzny (Target Discovery Institute, University of Oxford) , Simon Davis (University of Oxford) , Ming Yang (Target Discovery Institute, University of Oxford; The Francis Crick Institute) , Wei Ge (University of Oxford) , Justin L. P. Benesch (University of Oxford) , Benedikt M. Kessler (Target Discovery Institute, University of Oxford) , Peter J. Ratcliffe (Target Discovery Institute, University of Oxford) , Matthew E. Cockman (Target Discovery Institute, University of Oxford; The Francis Crick Institute) , Roman Fischer (Target Discovery Institute, University of Oxford) , Pablo Wappner (Instituto Leloir) , Rasheduzzaman Chowdhury (University of Oxford) , Mathew L. Coleman (University of Birmingham) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology , VOL 14 , PAGES 688 - 695

State: Published (Approved)
Published: June 2018

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.

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I04-Macromolecular Crystallography

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