Protein arginine methylation in mammals: who, what, and why

Abstract

The covalent marking of proteins by methyl group addition to arginine residues can promote their recognition by binding partners or can modulate their biological activity. A small family of gene products that catalyze such methylation reactions in eukaryotes (PRMTs) works in conjunction with a changing cast of associated subunits to recognize distinct cellular substrates. These reactions display many of the attributes of reversible covalent modifications such as protein phosphorylation or protein lysine methylation; however, it is unclear to what extent protein arginine demethylation occurs. Physiological roles for protein arginine methylation have been established in signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation.

Figure 1. Types of methylation on arginine residues

Types I, II and III PRMTs generate monomethylarginine (MMAω) on one of the terminal (ω) guanidino nitrogen atoms. These two nitrogen atoms are equivalent. The subsequent generation of asymmetric dimethylarginine (ADMA) is catalyzed by type I enzymes, and the production of symmetric dimethylarginine (SDMA) is catalyzed by type II enzymes. Type III PRMTs only monomethylate. Type IV enzyme activity that catalyzes the monomethylation of the internal guanidino nitrogen atom has only been described in yeast. The type of methylation reactions catalyzed by PRMT7, FBXO11, and Hsl7 are still being established, and are thus marked with an asterisk (see text).

Figure 2. The protein arginine methyltransferase family

The mammalian PRMT family currently contains nine highly related members; all harbor signature motifs I, post-I, II, and III, and the conserved THW loop (in black bars). FBXO11 might have arginine methyltransferase activity, but is not structurally related to the other PRMTs and required “forced” alignments to identify putative signature motifs (in gray bars). Protein domains that might assist in substrate recognition are marked in gray boxes. The accession numbers for the PRMTs are as follows: hPRMT1 (AAF62893), hPRMT2 (AAH00727), hPRMT3 (AAC39837), hCARM1 (NP_954592), hPRMT5 (AAF04502), hPRMT6 (Q96LA8), hPRMT7 (NP_061896), mPRMT8 (DAA01382), hPRMT9 (AAH64403) and mFBXO11 (AAI28480).

Figure 3. Arginine methylation of histone H3 and H4 N-terminal tails

The sites of PRMT-mediated methylation on the histone tails are noted. H3R2 methylation antagonizes the docking of a number of effector proteins, including those containing chromo, PHD, Tudor, and WD40 domains. H3R2 methylation structurally impedes the binding of H3K4me3 recognition domains and also prevents H3K4 methylation by the MLL1 complex. The first 5 residues of histones H2A and H4 are identical, and H2A is also methylated at the R3 position.