JMJD5 is a human arginyl C-3 hydroxylase

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.

Adventures in Defining Roles of Oxygenases in the Regulation of Protein Biosynthesis

“…JMJD6 has also been assigned by others as an N ‐methylarginyl histone demethylase,, but our evidence (as supported by some others) is that it is a lysyl C‐5 hydroxylase acting on both RNA splicing regulatory proteins and histone tails (Figure A) ,. JMJD5 is interesting because, like bacterial YcfD, it is an arginyl C‐3 hydroxylase, catalysing production of the (3 R )‐hydroxylated product (Figure B) . As for FIH catalysed ARD‐hydroxylation, none of the other JmjC hydroxylase catalysed reactions have as yet been shown to have ‘switch like’ effects on the roles/selectivities of their substrates.…”

Shared PKS Module in Biosynthesis of Synergistic Laxaphycins

“…The JmjC-like cupin 8 family (pfam13621) of proteins are Fe(II) or Zn(II) and α-ketoglutarate (α-KG) dependent oxygenases and act as hydroxylases and demethylases (Hewitson et al, 2002;Markolovic et al, 2016). There are examples of hydroxylation of Asn, Asp, His, Lys, Arg, and RNA in human and animal proteins (Wilkins et al, 2018). The activity of cupin 8 is specific to the amino acid position in the peptide.…”

The emerging roles of ribosomal histidyl hydroxylases in cell biology, physiology and disease

“…Phylogenetic tree constructed using iTOL online software [ 80 ] in unrooted tree format using tree data derived from Clustal Omega alignment of the following human protein sequences; MINA (Q8IUF8), NO66 (Q9H6W3), JMJD4 (Q9H9V9), JMJD5 (Q8N371), JMJD6 (Q6NYC1), JMJD7 (POC870), JMJD8 (Q96S16), TYW5 (A2RUC4), FIH (HIF1AN; Q9NWT6) and HSPBAP1 (Q96EW2). Primary biochemical specificities are indicated by His (histidyl hydroxylase), Lys (lysyl hydroxylase), Arg (arginyl hydroxylase), Asn (asparaginyl hydroxylase), yW-72 (hydroxylase of modified Wybutosine nucleoside in tRNAPhe) or ‘?’ (unknown) [ 6 , 9 , 11 , 81 – 83 ]. d Ribosomal oxygenases target important functional domains within the ribosome.…”