Optimal translational termination requires C4 lysyl hydroxylation of eRF1.
Efficient stop codon recognition and peptidyl-tRNA hydrolysis are essential in order to terminate translational elongation and maintain protein sequence fidelity. Eukaryotic translational termination is mediated by a release factor complex that includes eukaryotic release factor 1 (eRF1) and eRF3. The N terminus of eRF1 contains highly conserved sequence motifs that couple stop codon recognition at the ribosomal A site to peptidyl-tRNA hydrolysis. We reveal that Jumonji domain-containing 4 (Jmjd4), a 2-oxoglutarate- and Fe(II)-dependent oxygenase, catalyzes carbon 4 (C4) lysyl hydroxylation of eRF1. This posttranslational modification takes place at an invariant lysine within the eRF1 NIKS motif and is required for optimal translational termination efficiency. These findings further highlight the role of 2-oxoglutarate/Fe(II) oxygenases in fundamental cellular processes and provide additional evidence that ensuring fidelity of protein translation is a major role of hydroxylation.
Centre for Cellular and Molecular Physiology, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.
Tianshu
T
Feng
Centre for Cellular and Molecular Physiology, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.
Atsushi
A
Yamamoto
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
Sarah E
SE
Wilkins
Engelhardt Institute of Molecular Biology, the Russian Academy of Sciences, 119991 Moscow, Russia.
Elizaveta
E
Sokolova
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Luke A
LA
Yates
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
Martin
M
Münzel
Centre for Cellular and Molecular Physiology, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.
Pooja
P
Singh
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
Richard J
RJ
Hopkinson
Target Discovery Institute, Nuffield Department of Medicine, Oxford University, Roosevelt Drive, Oxford OX3 7FZ, UK.
Roman
R
Fischer
Centre for Cellular and Molecular Physiology, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.
Matthew E
ME
Cockman
Centre for Cellular and Molecular Physiology, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.
Jake
J
Shelley
Biochemistry Department and Proteomics Core, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA.
David C
DC
Trudgian
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, Germany.
Johannes
J
Schödel
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
James S O
JS
McCullagh
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
Wei
W
Ge
Target Discovery Institute, Nuffield Department of Medicine, Oxford University, Roosevelt Drive, Oxford OX3 7FZ, UK.
Benedikt M
BM
Kessler
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Robert J
RJ
Gilbert
Engelhardt Institute of Molecular Biology, the Russian Academy of Sciences, 119991 Moscow, Russia.
Ludmila Y
LY
Frolova
Engelhardt Institute of Molecular Biology, the Russian Academy of Sciences, 119991 Moscow, Russia.
Elena
E
Alkalaeva
Centre for Cellular and Molecular Physiology, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.
Peter J
PJ
Ratcliffe
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
Christopher J
CJ
Schofield
Centre for Cellular and Molecular Physiology, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK. Electronic address: m.coleman@bham.ac.uk.
Mathew L
ML
Coleman
D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D045744:Cell Line, Tumor; D018388:Codon, Terminator; D005786:Gene Expression Regulation; D006367:HeLa Cells; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D006900:Hydroxylation; D056484:Jumonji Domain-Containing Histone Demethylases; D006899:Mixed Function Oxygenases / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010443:Peptide Chain Termination, Translational / Q000235:genetics*; D010454:Peptide Termination Factors / Q000737:chemistry*; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
D018388:Codon, Terminator; C489002:ETF1 protein, human; D010454:Peptide Termination Factors; D006899:Mixed Function Oxygenases; D056466:Histone Demethylases; C587922:JMJD4 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases