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

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.Structural, biochemical and cellular studies reveal JMJD7 to be a Jumonji-C oxygenase that catalyzes (3S)-lysyl hydroxylation of the translation factor family of GTPases, DRG1 and DRG2.

[1]  J. Inoue,et al.  Independent stabilizations of polysomal Drg1/Dfrp1 complex and non-polysomal Drg2/Dfrp2 complex in mammalian cells. , 2009, Biochemical and biophysical research communications.

[2]  Paul Bowness,et al.  Discovery of Candidate Serum Proteomic and Metabolomic Biomarkers in Ankylosing Spondylitis* , 2011, Molecular & Cellular Proteomics.

[3]  R. Trievel,et al.  Crystal Structure and Functional Analysis of JMJD5 Indicate an Alternate Specificity and Function , 2012, Molecular and Cellular Biology.

[4]  Vincent B. Chen,et al.  Correspondence e-mail: , 2000 .

[5]  Christopher J Schofield,et al.  Structure-function relationships of human JmjC oxygenases-demethylases versus hydroxylases. , 2016, Current opinion in structural biology.

[6]  C. Robinson,et al.  Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans. , 2012, Nature chemical biology.

[7]  Weston B Struwe,et al.  High-resolution mass spectrometry of small molecules bound to membrane proteins , 2016, Nature Methods.

[8]  M. Coleman,et al.  OH, the Places You'll Go! Hydroxylation, Gene Expression, and Cancer. , 2015, Molecular cell.

[9]  C. Schofield,et al.  Protein Hydroxylation Catalyzed by 2-Oxoglutarate-dependent Oxygenases* , 2015, The Journal of Biological Chemistry.

[10]  S. Mohammed,et al.  Optimal Synthetic Glycosylation of a Therapeutic Antibody , 2016, Angewandte Chemie.

[11]  Kevin Cowtan,et al.  research papers Acta Crystallographica Section D Biological , 2005 .

[12]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[13]  C. Schofield,et al.  Mechanisms of human histone and nucleic acid demethylases. , 2012, Current opinion in chemical biology.

[14]  Clemens Vonrhein,et al.  Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER , 2012, Acta crystallographica. Section D, Biological crystallography.

[15]  D. Lu,et al.  Molecular Cloning and Expression of Two Closely Related GTP-binding Proteins from Zebrafish , 2004, DNA sequence : the journal of DNA sequencing and mapping.

[16]  M. Coleman,et al.  Modifying the maker: Oxygenases target ribosome biology , 2015, Translation.

[17]  Randy J. Read,et al.  Phenix - a comprehensive python-based system for macromolecular structure solution , 2012 .

[18]  C. Schofield,et al.  Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation , 2014, Proceedings of the National Academy of Sciences.

[19]  Monica Mantri,et al.  Autocatalysed oxidative modifications to 2‐oxoglutarate dependent oxygenases , 2012, The FEBS journal.

[20]  P. Ratcliffe,et al.  Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth , 2014, Proceedings of the National Academy of Sciences.

[21]  P. Ratcliffe,et al.  FIH‐Dependent Asparaginyl Hydroxylation of Ankyrin Repeat Domain‐Containing Proteins , 2009, Annals of the New York Academy of Sciences.

[22]  J. Inoue,et al.  Identification of DRG family regulatory proteins (DFRPs): specific regulation of DRG1 and DRG2 , 2005, Genes to cells : devoted to molecular & cellular mechanisms.

[23]  U. Oppermann,et al.  The roles of Jumonji-type oxygenases in human disease , 2014, Epigenomics.

[24]  P. Ratcliffe,et al.  Pharmacological targeting of the HIF hydroxylases--A new field in medicine development. , 2016, Molecular aspects of medicine.

[25]  Detlef D. Leipe,et al.  Classification and evolution of P-loop GTPases and related ATPases. , 2002, Journal of molecular biology.

[26]  P. Ratcliffe,et al.  Factor-inhibiting hypoxia-inducible factor (FIH) catalyses the post-translational hydroxylation of histidinyl residues within ankyrin repeat domains , 2011, The FEBS journal.

[27]  Yi Zhang,et al.  JmjC-domain-containing proteins and histone demethylation , 2006, Nature Reviews Genetics.

[28]  C. Schofield,et al.  Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases , 2016, Nature Communications.

[29]  C. Schofield,et al.  Inhibition of 2-oxoglutarate dependent oxygenases. , 2011, Chemical Society reviews.

[30]  G. Semenza,et al.  Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. , 2014, Annual review of pathology.

[31]  J. Inoue,et al.  Cloning and characterization of Xenopus laevis drg2, a member of the developmentally regulated GTP-binding protein subfamily. , 2003, Gene.

[32]  Randy J. Read,et al.  Acta Crystallographica Section D Biological , 2003 .

[33]  Alan Brown,et al.  Structural basis for stop codon recognition in eukaryotes , 2015, Nature.

[34]  M. Mann,et al.  Jmjd6 Catalyses Lysyl-Hydroxylation of U2AF65, a Protein Associated with RNA Splicing , 2009, Science.

[35]  J. Elkins,et al.  Structure of Factor-inhibiting Hypoxia-inducible Factor (HIF) Reveals Mechanism of Oxidative Modification of HIF-1α* , 2003, The Journal of Biological Chemistry.

[36]  D. Barford,et al.  The Crystal Structure of Human Eukaryotic Release Factor eRF1—Mechanism of Stop Codon Recognition and Peptidyl-tRNA Hydrolysis , 2000, Cell.

[37]  B. Witkop.  The application of Hudson's lactone rule toγ- andδ-hydroxyamino acids and the question of the configuration ofδ-hydroxy-l-lysine from collagen , 1956, Experientia.

[38]  Joseph T. Glessner,et al.  Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population , 2014, Molecular Autism.

[39]  Li Lu,et al.  DRG1 is a potential oncogene in lung adenocarcinoma and promotes tumor progression via spindle checkpoint signaling regulation , 2016, Oncotarget.

[40]  M. Lübbert,et al.  Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy , 2016, Clinical Epigenetics.

[41]  K. Tārs,et al.  Human carnitine biosynthesis proceeds via (2S,3S)-3-hydroxy-N ε-trimethyllysine† †Electronic supplementary information (ESI) available: Synthesis procedures, assay conditions, NMR assignments and spectra, and MS analyses. See DOI: 10.1039/c6cc08381a Click here for additional data file. , 2016, Chemical communications.

[42]  Monica Mantri,et al.  The 2‐Oxoglutarate‐Dependent Oxygenase JMJD6 Catalyses Oxidation of Lysine Residues to give 5S‐Hydroxylysine Residues , 2011, Chembiochem : a European journal of chemical biology.

[43]  K. Kavanagh,et al.  Ribosomal Oxygenases are Structurally Conserved from Prokaryotes to Humans , 2014, Nature.

[44]  L. Frolova,et al.  Optimal Translational Termination Requires C4 Lysyl Hydroxylation of eRF1 , 2014, Molecular cell.

[45]  Steven J. M. Jones,et al.  Integrated genomic characterization of endometrial carcinoma , 2013, Nature.

[46]  J. Powers,et al.  Irreversible inhibitors of serine, cysteine, and threonine proteases. , 2002, Chemical reviews.

[47]  Z. Otwinowski,et al.  [20] Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[48]  Sarah Curran,et al.  A Common Variant in DRD3 Receptor Is Associated with Autism Spectrum Disorder , 2009, Biological Psychiatry.

[49]  R. Muschel,et al.  Novel MMP-9 Substrates in Cancer Cells Revealed by a Label-free Quantitative Proteomics Approach*S , 2008, Molecular & Cellular Proteomics.

[50]  J. Bravo,et al.  Human Drg1 is a potassium‐dependent GTPase enhanced by Lerepo4 , 2013, The FEBS journal.

[51]  Benjamin J. Nelson,et al.  Association of DRG1 and DRG2 with Ribosomes from Pea, Arabidopsis, and Yeast , 2009, International Journal of Plant Sciences.

[52]  T. Becker,et al.  Structure of a human translation termination complex , 2015, Nucleic acids research.

[53]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[54]  James E. Bray,et al.  Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity , 2007, Nature.

[55]  B. Séraphin,et al.  The highly conserved eukaryotic DRG factors are required for efficient translation in a manner redundant with the putative RNA helicase Slh1 , 2010, Nucleic acids research.

[56]  O. Nureki,et al.  Crystal structure of a novel JmjC-domain-containing protein, TYW5, involved in tRNA modification , 2010, Nucleic acids research.

[57]  K. Kivirikko,et al.  Collagens and collagen-related diseases , 2001, Annals of medicine.

[58]  P. Ratcliffe,et al.  Disruption of dimerization and substrate phosphorylation inhibit factor inhibiting hypoxia-inducible factor (FIH) activity. , 2004, The Biochemical journal.

[59]  Jeong Woo Park,et al.  DRG2 Regulates G2/M Progression via the Cyclin B1-Cdk1 Complex , 2016, Molecules and cells.

[60]  B. V. van Bon,et al.  Diagnostic exome sequencing in persons with severe intellectual disability. , 2012, The New England journal of medicine.

[61]  Sandrea M. Francis,et al.  Rbg1–Tma46 dimer structure reveals new functional domains and their role in polysome recruitment , 2012, Nucleic acids research.

[62]  Randy J. Read,et al.  Phaser crystallographic software , 2007, Journal of applied crystallography.

[63]  C. Schofield,et al.  2-Oxoglutarate-Dependent Oxygenases. , 2018, Annual review of biochemistry.