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Ribosomal oxygenases are structurally conserved from prokaryotes to humans

DOI: 10.1038/nature13263 DOI Help
PMID: 4066111 PMID Help

Authors: Rasheduzzaman Chowdhury (The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford) , Rok Sekirnik (The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford) , Nigel Brissett (Genome Damage and Stability Centre, University of Sussex) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , Chia-hua Ho (The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford) , Stanley Ng (Structural Genomics Consortium, University of Oxford) , Ian Clifton (The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford) , Wei Ge (The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford) , Nadia J. Kershaw (The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford) , Gavin C. Fox (Synchrotron SOLEIL) , Joao Muniz (Structural Genomics Consortium, University of Oxford) , Melanie Vollmar (Structural Genomics Consortium, University of Oxford, Diamond Light Source) , Claire Phillips (Structural Genomics Consortium, University of Oxford) , Ewa S. Pilka (Structural Genomics Consortium, University of Oxford) , Kathryn L. Kavanagh (Structural Genomics Consortium, University of Oxford) , Frank Von Delft (University of Oxford, Diamond Light Source) , Udo Oppermann (NIHR Oxford Biomedical Research Unit, Botnar Research Centre) , Michael Mcdonough (The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford) , Aidan J. Doherty (Genome Damage and Stability Centre, University of Sussex) , Christopher J. Schofield (The Department of Chemistry and Oxford Centre for Integrative Systems Biology, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 509 (7505) , PAGES 422 - 426

State: Published (Approved)
Published: May 2014
Diamond Proposal Number(s): 7495

Open Access Open Access

Abstract: 2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components1, 2 and in the hydroxylation of transcription factors3 and splicing factor proteins4. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA5, 6, 7 and ribosomal proteins8 have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy9, 10, 11, 12. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans8 raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone Nε-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases.

Journal Keywords: Catalytic; Conserved; Eukaryota; Humans; Models; Molecular; Oxygenases; Phylogeny; Prokaryotic; Protein; Tertiary; Ribosomes; Sequence Alignment

Subject Areas: Biology and Bio-materials


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