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Review
. 2017 Sep;74(18):3305-3315.
doi: 10.1007/s00018-017-2515-z. Epub 2017 Mar 31.

Protein arginine methylation: a prominent modification and its demethylation

Juste Wesche  1 , Sarah Kühn  1 , Benedikt M Kessler  2 , Maayan Salton  3 , Alexander Wolf  4
Affiliations
Review

Protein arginine methylation: a prominent modification and its demethylation

Juste Wesche et al. Cell Mol Life Sci. 2017 Sep.

Abstract

Arginine methylation of histones is one mechanism of epigenetic regulation in eukaryotic cells. Methylarginines can also be found in non-histone proteins involved in various different processes in a cell. An enzyme family of nine protein arginine methyltransferases catalyses the addition of methyl groups on arginines of histone and non-histone proteins, resulting in either mono- or dimethylated-arginine residues. The reversibility of histone modifications is an essential feature of epigenetic regulation to respond to changes in environmental factors, signalling events, or metabolic alterations. Prominent histone modifications like lysine acetylation and lysine methylation are reversible. Enzyme family pairs have been identified, with each pair of lysine acetyltransferases/deacetylases and lysine methyltransferases/demethylases operating complementarily to generate or erase lysine modifications. Several analyses also indicate a reversible nature of arginine methylation, but the enzymes facilitating direct removal of methyl moieties from arginine residues in proteins have been discussed controversially. Differing reports have been seen for initially characterized putative candidates, like peptidyl arginine deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most recent cellular, biochemical, and mass spectrometry work on arginine methylation and its reversible nature with a special focus on putative arginine demethylases, including the enzyme superfamily of Fe(II) and 2-oxoglutarate-dependent oxygenases.

Keywords: Histone modifications; KDM; KDM2A; KDM3A; KDM4E; KDM5C; KDM6B; KDM7B; KMT; Liquid chromatography–tandem mass spectrometry; PHF8; Post-translational modifications.

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Figures

Fig. 1
Fig. 1
Counteracting pair of enzyme families regulates methylation of lysine residues in proteins. Mono-, di-, or tri-methylation (Kme1, Kme2, and Kme3) of lysine at the ε-amino group is catalyzed by lysine methyltransferases (KMTs) (a). This modification is reversible and can be erased by lysine demethylases (KDMs) (a). The protein arginine methyltransferases (PRMTs) can modify the guanidinium group of arginine residues and result in either mono-methylated (Rme1) or symmetric (Rme2s) or asymmetric (Rme2a) di-methylated arginine (b). Presently, an arginine demethylation activity in vivo has been described for Jumonji domain containing protein 6 (Jmjd6) (b)
Fig. 2
Fig. 2
General procedure of large-scale mass spectrometry analysis of cellular arginine methylomes. The first step of the proteomic workflow is protein extraction and digestion with a sequence-specific protease. Cells might be pretreated with stable-isotope labeling methods (SILAC). To enrich the usually low abundant peptides with post-translational modifications, an immunoaffinity purification step has been established. Prior to LC-MS analysis, the peptide mixture is incubated with antibodies detecting specific PTMs of interest
Fig. 3
Fig. 3
Fe(II) and 2-oxoglutarate-dependent oxygenases. The protein superfamily of Fe(II) and 2-oxoglutrate-dependent oxygenases (2OG oxygenase) transfers oxygen (O2) onto a substrate. This can either result in a stable protein hydroxylation (a) or in a lysine demethylation (b). Substrate oxidation is always coupled to decarboxylation of the co-substrate 2-oxoglutarate, leading to succinate and CO2. 2OG oxygenase-catalyzed protein hydroxylation is exemplified by Ogfod1, which hydroxylates proline 62 in the human ribosomal protein RPS23 [58, 59] (a), but has also been described for Arg, Asp, Asn, His, and Lys in different proteins [57]. Alternatively, hydroxylation can occur on a methyl group of methylated lysine, which then results in release of formaldehyde and demethylation of the lysine residue (b). Protein hydroxylases and lysine demethylases (KDMs) comprise two distinct subgroups of 2OG oxygenases (c). They all share one common structural motif, the double stranded β-helix (DSBH) fold (or jumonji fold) consisting of eight β-sheets. A conserved HxD/E…H motif coordinates the binding of co-factor Fe(II) (d). Some members of the 2OG oxygenase family have been assigned a putative arginine demethylation activity (e)
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