Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
ReviewReaders of histone methylarginine marks☆
Introduction
Arginine has the longest side chain of the 20 naturally occurring amino acids, and the end of the side chain bears a positive charge — properties that make it a good anchor for potential protein–protein interactions. Its guanidine group contains five potential hydrogen bond donors that can be used to stabilize interactions with DNA, RNA and proteins [1]. The methylation of arginine changes its shape, does not alter the charge, but removes potential hydrogen bond donors, which would potentially inhibit certain interactions [2]. Importantly, the methylation of arginine residues can also increase their affinity to aromatic rings in cation–pi interactions, thus promoting other interactions [3]. So, protein arginine methylation can both positively and negatively regulate protein–protein interactions, examples of which will be highlighted here.
Three distinct types of methylated arginine residues occur in mammalian cells (Fig. 1A). The most abundant type is omega-NG,NG-dimethylarginine [4]. In this case, two methyl groups are placed on one of the terminal nitrogen atoms of the guanidino group, and this derivative is commonly referred to as asymmetric dimethylarginine (ADMA). Two other derivatives occur at levels less than 50% that of ADMA. These include the symmetric dimethylated derivative, where one methyl group is placed on each of the terminal guanidino nitrogens (omega-NG,N′G-dimethylarginine; commonly referred to as SDMA) and the monomethylated derivative with a single methyl group on the terminal nitrogen atom (omega-NG-monomethylarginine; commonly referred to as MMA). The three types of arginine methylation are catalyzed by a family of nine AdoMet-dependent enzymes called the protein arginine methyltransferases (PRMTs). Arginine demethylation activity has been reported for the JmjC-domain-containing protein JMJD6 [5], [6].
The PRMTs are classified according to the type of methylation they are able to catalyze. Types I, II and III are able to generate a MMA. Type I enzymes (PRMT1, PRMT2, PRMT3, PRMT4/CARM1, PRMT6, and PRMT8) perform a second methylation step to generate the ADMA mark, and the Type II enzyme (PRMT5) generates the SDMA mark. The Type III enzyme (PRMT7) only generates a MMA mark. Most MMA marks are presumed to serve as precursors for the subsequent methylation by Type I and II PRMTs, but certain proteins exist in a heavily monomethylated state [7]. Sequence analysis of all PRMTs shows a highly conserved catalytic core region, containing the signature methyltransferase motifs I, post-I, II and III, which are characteristic of the super-family of seven-beta strand methyltransferases. They also harbor additional “double E” (two glutamate residues) and “THW” (threonine–histidine–tryptophan) sequence motifs, which are particular to the PRMT subfamily of methyltransferases [1]. The catalytic core is highly conserved at the structural level, as revealed by the crystal structure of PRMT1, PRMT3, PRMT4 and PRMT5 [8], [9], [10], [11], [12], [13], [14].
It should be noted that the metabolic cost of arginine methylation is high, requiring the use of 12 ATP molecules per methylation event [15]. The fact that such an “expensive” PTM is abundant and has not been lost to evolutionary pressure underscores the biological importance of the methylated motifs that have survived.
Section snippets
Sites of arginine methylation on histones
Arginine methylation is an abundant posttranslational modification (PTM), with about 0.5% of arginine residues methylated in mammalian tissues [4], [16], and roughly 2% of arginine residues methylated in rat liver nuclei [17]. The large majority of this type of protein methylation occurs on non-histone proteins and most of these substrates are methylated on Glycine/Arginine-Rich (GAR) motifs. Many of these substrates have recently been cataloged by mass spectrometric analysis [18], [19], [20].
Tudor domains
The seminal discovery, made by Tony Pawson over twenty years ago, that SRC homology 2 (SH2) domains bind to short protein motifs that are tyrosine phosphorylated [23], led to the realization that different modular domains bind distinct types of PTMs [24]. For example, lysine methylated motifs are bound by at least eight different domain types — Chromo, PHD, MBT, Tudor, PWWP, Ank, BAH and WD40 domains. Currently, the only protein domain family known to bind methylated arginine motifs is the
Tudor domains bind methyllysine and methylarginine motifs
The pioneering work on Tudor domain biochemistry and structure involved studies using the human survival motor neuron (SMN) protein [29], [30], which is mutated in spinal muscular atrophy syndrome [31]. SMN harbors a single Tudor domain and was one of the first proteins identified to interact with a methylated motif [29], [32], along with the chromo domain-containing protein, HP1 [33], [34]. It soon became clear that Tudor domains bind not only methylarginine motifs, but also methyl-lysine
SMN
Spinal muscular atrophy (SMA) is an autosomal recessive disease resulting from the loss of SMN1 gene function. SMA is among the leading genetic causes of infant death, with a prevalence of ~ 1 in 6000 live births [44]. SMN regulates the assembly of RNA–protein complexes called small nuclear ribonucleoproteins (snRNPs), and binds the spliceosomal core proteins SmD1, SmD3 and SmB/B′ through its Tudor domain. This binding is driven by symmetric methylation of arginine residues in the C-terminal
The H3R2 site as a node of transcriptional regulation — PHD and WD40 domains
The H3K4 site is a major epigenetic mark, which when tri-methylated defines active promoters. H3K4 methylation and effector molecule recognition can be impacted by methylation of H3R2. H3R2me2a is a major mark deposited by PRMT6 [86], [87], [88]. Methylation of the H3R2 site essentially prevents the MLL1 complex from methylating H3K4 [87]. However, PRMT6 can strongly methylate H3K4me1 and H3K4me2 peptides, and weakly methylate a H3K4me3 peptide, so dually modified H3R2me2aK4me3 histone tails
The PAF1 complex
The transcriptional coactivator, CARM1, deposits the H3R17me2a mark. Peptides bearing this mark were used to pull-down interacting proteins from a HeLa nuclear extract [104]. The methyl-dependent interacting proteins were identified by mass spectrometry, and they turned out to be members of the transcription elongation-associated PAF1 complex. Consistent with this finding, loss of CARM1 results in a reduction of the PAF complex at estrogen-response elements. Unfortunately, it is not clear which
Chemical compounds that mimic an aromatic cage
Structural analysis has made it abundantly clear that most of the domains that “read” methylarginine marks, do so by using a “cage” in which four faces consist of aromatic residues. An exciting new avenue of research is the synthesis of artificial aromatic cages that function as receptors and recognize methylarginine marks. The Waters group has synthesized these small chemical probes that mimic the aromatic cages observed in protein structure [113]. One of these synthetic receptors (A2D)
Perspectives
It is probable that we have identified all the arginine methyltransferases within the “classic” PRMT family. It is possible that convergent evolution has generated other classes of arginine methyltransferases, as it has for lysine methyltransferases and demethylases. Also, the search for additional “readers” of arginine methylated motifs will be important to help us understand the mechanisms of action of this PTM. Because of the abundance of this modification, it is likely that there will be
Acknowledgements
Mark T. Bedford is supported by CPRIT funding (RP110471) and a NIH grant (DK062248). Sitaram Gayatri is an Epigenetic Scholar and is supported by the Center for Cancer Epigenetics (CCE) at MD Anderson Cancer Center.
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This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.