Review
Readers of histone methylarginine marks

https://doi.org/10.1016/j.bbagrm.2014.02.015Get rights and content

Highlights

  • 0.5% of all arginine residues in the cell are methylated.

  • There are three types of arginine methylation: mono, asymmetric & symmetric.

  • The primary “readers” of methylarginine marks are Tudor domain-containing proteins.

Abstract

Arginine methylation is a common posttranslational modification (PTM) that alters roughly 0.5% of all arginine residues in the cells. There are three types of arginine methylation: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). These three PTMs are enriched on RNA-binding proteins and on histones, and also impact signal transduction cascades. To date, over thirty arginine methylation sites have been cataloged on the different core histones. These modifications alter protein structure, impact interactions with DNA, and also generate docking sites for effector molecules. The primary “readers” of methylarginine marks are Tudor domain-containing proteins. The complete family of thirty-six Tudor domain-containing proteins has yet to be fully characterized, but at least ten bind methyllysine motifs and eight bind methylarginine motifs. In this review, we will highlight the biological roles of the Tudor domains that interact with arginine methylated motifs, and also address other types of interactions that are regulated by these particular PTMs. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.

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,NG-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.

References (130)

  • R.E. Boswell et al.

    Tudor, a gene required for assembly of the germ plasm in Drosophila melanogaster

    Cell

    (1985)
  • S. Maurer-Stroh et al.

    The Tudor domain ‘Royal Family’: Tudor, plant Agenet, Chromo, PWWP and MBT domains

    Trends Biochem. Sci.

    (2003)
  • W.J. Friesen et al.

    SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets

    Mol. Cell

    (2001)
  • M.V. Botuyan et al.

    Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair

    Cell

    (2006)
  • D. Cheng et al.

    The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing

    Mol. Cell

    (2007)
  • J. Rappsilber et al.

    SPF30 is an essential human splicing factor required for assembly of the U4/U5/U6 tri-small nuclear ribonucleoprotein into the spliceosome

    J. Biol. Chem.

    (2001)
  • J. Cote et al.

    Tudor domains bind symmetrical dimethylated arginines

    J. Biol. Chem.

    (2005)
  • Y. Yang et al.

    TDRD3 is an effector molecule for arginine-methylated histone marks

    Mol. Cell

    (2010)
  • Y. Yang et al.

    Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation

    Mol. Cell.

    (2014)
  • S. Zheng et al.

    Arginine methylation-dependent reader–writer interplay governs growth control by E2F-1

    Mol. Cell.

    (2013)
  • T. Valineva et al.

    The transcriptional co-activator protein p100 recruits histone acetyltransferase activity to STAT6 and mediates interaction between the CREB-binding protein and STAT6

    J. Biol. Chem.

    (2005)
  • Y. Feng et al.

    Histone H4 acetylation differentially modulates arginine methylation by an in Cis mechanism

    J. Biol. Chem.

    (2011)
  • X. Gao et al.

    Tudor staphylococcal nuclease (Tudor-SN) participates in small ribonucleoprotein (snRNP) assembly via interacting with symmetrically dimethylated Sm proteins

    J. Biol. Chem.

    (2012)
  • M.A. Blanco et al.

    Identification of staphylococcal nuclease domain-containing 1 (SND1) as a Metadherin-interacting protein with metastasis-promoting functions

    J. Biol. Chem.

    (2011)
  • F.S. Lamb et al.

    Complex RNA processing of TDRKH, a novel gene encoding the putative RNA-binding Tudor and KH domains

    Gene

    (2000)
  • A. Vasileva et al.

    TDRD6 is required for spermiogenesis, chromatoid body architecture, and regulation of miRNA expression

    Curr. Biol.

    (2009)
  • A.N. Iberg et al.

    Arginine methylation of the histone h3 tail impedes effector binding

    J. Biol. Chem.

    (2008)
  • J. Michaud-Levesque et al.

    Thrombospondin-1 is a transcriptional repression target of PRMT6

    J. Biol. Chem.

    (2009)
  • E. Rajakumara et al.

    PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression

    Mol. Cell

    (2011)
  • M. Fiedler et al.

    Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex

    Mol. Cell

    (2008)
  • C.C. Yuan et al.

    Histone H3R2 symmetric dimethylation and histone H3K4 trimethylation are tightly correlated in eukaryotic genomes

    Cell Rep.

    (2012)
  • R.M. Hughes et al.

    Arginine methylation in a beta-hairpin peptide: implications for Arg–pi interactions, DeltaCp(o), and the cold denatured state

    J. Am. Chem. Soc.

    (2006)
  • W.K. Paik et al.

    Natural Occurrence of Various Methylated Amino Acid Derivatives

    (1980)
  • B. Chang et al.

    JMJD6 is a histone arginine demethylase

    Science

    (2007)
  • S. Dhar et al.

    Loss of the major Type I arginine methyltransferase PRMT1 causes substrate scavenging by other PRMTs

    Sci. Rep.

    (2013)
  • S. Antonysamy et al.

    Crystal structure of the human PRMT5:MEP50 complex

    Proc. Natl. Acad. Sci. U. S. A.

    (2012)
  • M.C. Ho et al.

    Structure of the arginine methyltransferase PRMT5–MEP50 reveals a mechanism for substrate specificity

    PLoS One

    (2013)
  • L. Sun et al.

    Structural insights into protein arginine symmetric dimethylation by PRMT5

    Proc. Natl. Acad. Sci. U. S. A.

    (2011)
  • N. Troffer-Charlier et al.

    Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains

    EMBO J.

    (2007)
  • W.W. Yue et al.

    Insights into histone code syntax from structural and biochemical studies of CARM1 methyltransferase

    EMBO J.

    (2007)
  • X. Zhang et al.

    Crystal structure of the conserved core of protein arginine methyltransferase PRMT3

    EMBO J.

    (2000)
  • M. Matsuoka

    Epsilon-N-methylated lysine and guanidine-N-methylated arginine of proteins. 3. Presence and distribution in nature and mammals

    Seikagaku

    (1972)
  • M. Bremang et al.

    Mass spectrometry-based identification and characterisation of lysine and arginine methylation in the human proteome

    Mol. Biosyst.

    (2013)
  • F. Casadio et al.

    H3R42me2a is a histone modification with positive transcriptional effects

    Proc. Natl. Acad. Sci. U. S. A.

    (2013)
  • D. Anderson et al.

    Binding of SH2 domains of phospholipase C gamma 1, GAP, and Src to activated growth factor receptors

    Science

    (1990)
  • Y.L. Deribe et al.

    Post-translational modifications in signal integration

    Nat. Struct. Mol. Biol.

    (2010)
  • I. Callebaut et al.

    The human EBNA-2 coactivator p100: multidomain organization and relationship to the staphylococcal nuclease fold and to the Tudor protein involved in Drosophila melanogaster development

    Biochem. J.

    (1997)
  • P. Selenko et al.

    SMN Tudor domain structure and its interaction with the Sm proteins

    Nat. Struct. Biol.

    (2001)
  • S.J. Kolb et al.

    Spinal muscular atrophy: a timely review

    Arch. Neurol.

    (2011)
  • H. Brahms et al.

    Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B′ and the Sm-like protein LSm4, and their interaction with the SMN protein

    RNA

    (2001)
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    This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.

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