Abstract
Oxygenase-catalysed post-translational modifications of basic protein residues, including lysyl hydroxylations and Nε-methyl lysyl demethylations, have important cellular roles. Jumonji-C (JmjC) domain-containing protein 5 (JMJD5), which genetic studies reveal is essential in animal development, is reported as a histone Nε-methyl lysine demethylase (KDM). Here we report how extensive screening with peptides based on JMJD5 interacting proteins led to the finding that JMJD5 catalyses stereoselective C-3 hydroxylation of arginine residues in sequences from human regulator of chromosome condensation domain-containing protein 1 (RCCD1) and ribosomal protein S6 (RPS6). High-resolution crystallographic analyses reveal overall fold, active site and substrate binding/product release features supporting the assignment of JMJD5 as an arginine hydroxylase rather than a KDM. The results will be useful in the development of selective oxygenase inhibitors for the treatment of cancer and genetic diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arginine / chemistry*
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Arginine / metabolism
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Carrier Proteins / chemistry*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Catalytic Domain
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Cloning, Molecular
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Crystallography, X-Ray
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Gene Expression
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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Histone Demethylases / chemistry*
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Histone Demethylases / genetics
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Histone Demethylases / metabolism
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Humans
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Hydroxylation
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Kinetics
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Lysine / chemistry
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Lysine / metabolism
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Membrane Proteins / chemistry*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Models, Molecular
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Folding
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Protein Interaction Domains and Motifs
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Ribosomal Protein S6 / chemistry*
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Ribosomal Protein S6 / genetics
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Ribosomal Protein S6 / metabolism
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Stereoisomerism
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Substrate Specificity
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Thermodynamics
Substances
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Carrier Proteins
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Membrane Proteins
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RCCD1 protein, human
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Recombinant Proteins
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Ribosomal Protein S6
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Arginine
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Histone Demethylases
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KDM8 protein, human
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Lysine