RMTs methylate histone arginines

Stable Identifier
Homo sapiens
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Arginine methylation is a common post-translational modification; around 2% of arginine residues are methylated in rat liver nuclei (Boffa et al. 1977). Arginine can be methylated in 3 different ways: monomethylarginine (MMA); NG,NG-asymmetric dimethylarginine (ADMA) and NG,N'G-symmetric dimethylarginine (SDMA). The formation of MMA, ADMA and SDMA in mammalian cells is carried out by members of a family of nine protein arginine methyltransferases (PRMTs) (Bedford & Clarke 2009).

Type I, II and III PRMTs generate MMA on one of the two terminal guanidino nitrogen atoms. Subsequent generation of asymmetric dimethylarginine (ADMA) is catalysed by the type I enzymes PRMT1, PRMT2, PRMT3, co-activator-associated arginine methyltransferase 1 (CARM1), PRMT6 and PRMT8. Production of symmetric dimethylarginine (SDMA) is catalysed by the type II enzymes PRMT5 and PRMT7. On certain substrates, PRMT7 also functions as a type III enzyme, generating MMA only. PRMT9 activity has not been characterized. No known enzyme is capable of both ADMA and SDMA modifications. Arginine methylation is regarded as highly stable; no arginine demethylases are known (Yang & Bedford 2013).

Most PRMTs methylate glycine- and arginine-rich (GAR) motifs in their substrates (Boffa et al. 1977). CARM1 methylates a proline-, glycine- and methionine-rich (PGM) motif (Cheng et al. 2007). PRMT5 can dimethylate arginine residues in GAR and PGM motifs (Cheng et al. 2007, Branscombe et al. 2001).

PRMTs are widely expressed and are constitutively active as purified recombinant proteins. However, PRMT activity can be regulated through PTMs, association with regulatory proteins, subcellular compartmentalization and factors that affect enzyme-substrate interactions. The target sites of PRMTs are influenced by the presence of other PTMs on their substrates. The best characterized examples of this are for histones. Histone H3 lysine-19 acetylation (H3K18ac) primes the histone tail for asymmetric dimethylation at arginine-18 (H3R17me2a) by CARM1 (An et al. 2003, Daujat et al. 2002, Yue et al. 2007). H3 lysine-10 acetylation (H3K9ac) blocks arginine-9 symmetric dimethylation (H3R8me2s) by PRMT5 (Pal et al. 2004). H4R3me2a catalyzed by PRMT1 favours subsequent acetylation of the histone H4 tail (Huang et al. 2005). At the same time histone H4 lysine-5 acetylation (H4K5ac) makes the H4R3 motif a better substrate for PRMT5 compared with PRMT1, thereby moving the balance from an activating ADMA mark to a suppressive SDMA mark at the H4R3 motif (Feng et al. 2011). Finally methylation of Histone H3 on arginine-3 (H3R2me2a) by PRMT6 blocks methylation of H3 lysine-5 by the MLL complex (H3K4me3), and vice versa, methylation of H3K4me3 prevents H3R2me2a methylation (Guccione et al. 2007, Kirmizis et al. 2007, Hyllus et al. 2007). N.B. The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
Literature References
PubMed ID Title Journal Year
23235912 Protein arginine methyltransferases and cancer

Bedford, MT, Yang, Y

Nat. Rev. Cancer 2013
19150423 Protein arginine methylation in mammals: who, what, and why

Bedford, MT, Clarke, SG

Mol. Cell 2009
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