JMJD5 is a human arginyl C-3 hydroxylase

  • Nat Commun. 2018 Mar 21;9(1):1180. doi: 10.1038/s41467-018-03410-w.
Sarah E Wilkins  1 ,  Md Saiful Islam  1 ,  Joan M Gannon  1 ,  Suzana Markolovic  1 ,  Richard J Hopkinson  1  2 ,  Wei Ge  1 ,  Christopher J Schofield  3 ,  Rasheduzzaman Chowdhury  4  5
Affiliations
  • 1. The Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
  • 2. Leicester Institute of Structural and Chemical Biology and Department of Chemistry, University of Leicester, Lancaster Road, Leicester, LE1 7RH, UK.
  • 3. The Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK. [email protected].
  • 4. The Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK. [email protected].
  • 5. Stanford University School of Medicine, Department of Molecular and Cellular Physiology, Clark Center, Stanford, CA, 94305-5345, USA. [email protected].
PMID: 29563586 DOI: 10.1038/s41467-018-03410-w
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.