Arginine methylation ata glanceMark T. BedfordDepartment of Carcinogenesis, The University ofTexas M. D. Anderson Cancer Center, Smithville,TX 78957, USAe-mail: mtbedford@mdanderson.org

Journal of Cell Science 120, 4243-4246Published by The Company of Biologists 2007doi:10.1242/jcs.019885

Arginine methylation is a prevalentpost-translational modification found onboth nuclear and cytoplasmic proteins.The methylation of arginine residues iscatalyzed by the protein arginine N-methyltransferase (PRMT) family of

enzymes. Proteins that are argininemethylated are involved in a number ofdifferent cellular processes, includingtranscriptional regulation, RNAmetabolism and DNA damage repair(Bedford and Richard, 2005). MostPRMTs methylate glycine- andarginine-rich patches (GAR motifs)within their substrates. The complexityof the methylarginine mark is enhancedby the ability of this residue to bemethylated in three different ways onthe guanidino group: monomethylated(MMA), symmetrically dimethylated(sDMA) and asymmetricallydimethylated (aDMA), each of whichhas potentially different functionalconsequences.

Mammalian argininemethyltransferasesThere are three structurally defined typesof S-adenosylmethionine (AdoMet)-dependent methyltransferase (Katz et al.,2003). The largest class (Class I) hasa common seven-stranded �-sheetstructure. The Class II enzymes arethe SET lysine methyltransferases andClass III encompasses the membrane-associated methyltransferases. PRMTfamily members fall into Class I andharbor a set of four conserved sequencemotifs (I, post-I, II, and III) and a THWloop (Katz et al., 2003). Motifs I, post-Iand the THW loop form part of theAdoMet-binding pocket (Zhang et al.,2000). Ten mammalian PRMTs have beenidentified to date. Eight have been shownto catalyze the transfer of a methylgroup from AdoMet to a guanidinonitrogen of arginine, generating S-adenosylhomocysteine (AdoHcy) andmethylarginine. No activity has yet beendemonstrated for PRMT2 and PRMT9.

PRMTs are classified as type I, type II,type III or type IV enzymes. Types I, IIand III enzymes methylate the terminal(or �) guanidino nitrogen atoms. Type Iand type II enzymes all catalyze theformation of an MMA intermediate, thentype I PRMTs (PRMT1, 3, 4, 6 and 8)further catalyze the production ofaDMA, whereas type II PRMTs(PRMT5, PRMT7 and FBXO11)catalyze the formation of sDMA.PRMT7 also exhibits type III enzymaticactivity – the propensity to catalyze theformation of MMA on certain substratesand not proceed with sDMA catalysis. Atype IV enzyme that catalyzes themonomethylation of the internal (or �)guanidino nitrogen atom has beendescribed in yeast.

PRMT1PRMT1, the predominant mammaliantype I enzyme, was identified by sequencesimilarity to the yeast argininemethyltransferase Hmt1/Rmt1 (Lin et al.,1996). PRMT1 is broadly expressed andlocalizes to both the cytoplasm and thenucleus and has substrates in both thesecellular compartments (Herrmann et al.,2005). PRMT1 methylates a number ofhnRNP molecules, and this modificationplays a role in the shuttling of theseproteins between the cytoplasm and thenucleus (Herrmann et al., 2004). PRMT1also methylates histone H4 at arginine 3

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© Journal of Cell Science 2007 (120, pp. 4243-4246)

Arginine Methylation at a GlanceMark T. Bedford

PRMT5

PRMT7

PRMT1

PRMT3

CARM1/PRMT4

BRM/BRG1

CTCFL

BTG1

Protein interactionsincrease PRMT activity

Protein interactionsalter PRMT specificity

DAL-1

NUMAC

Regulation by PRMT-binding proteins

Protein interactionsdecrease PRMT activity

hCAF1

CARM1/PRMT4

CARM1/PRMT4

Kinase

Phosphorylation decreasesPRMT activity

Regulation by PTMs

H2N NH2

NH

(CH2)3

C

C

O

CH

Arginine

HNN

HNH3 +H+

H2N O

NH

(CH2)3

C

C

O

CH

HNN

H

Citrulline

PAD

Regulation by enzymes

Deimination of arginineblocks arginine methylation

Arginine demethylases

JMJD6

PRMT1

PMRT2

PRMT3

CARM1/PRMT4

PRMT5

PRMT6

PRMT7

PRMT8

PRMT9

FBXO11

SH3domain

Znfinger

TRP2

Fbox

Znfinger

Signature PRMT motifs: I Post I II III THW loop I Post I II III THW loop

361

433

531

608

637

375

692

394

843

845

Signature PRMT motifs

Motif IPost IMotif IIMotif IIITHW loop

-VLD/EVGxGxG-V/IxG/AxD/E-F/I/VDI/L/K-LR/KxxG

good sequence similarityweak sequence similarity

myr

Arginine methyltransferases

Arginine-methylated proteins

Chromatin-associatedproteins

Histone H4Histone H2APGC-1αSPT5TAFII68ZN5RIP140HMGA1a

PRMT1 PRMT3 CARM1/PRMT4 PRMT5 PRMT6 PRMT7

Histone H3Histone H2ACBPp300AIB1

Histone H4Histone H3Histone H2ASPT5FCP1

Histone H4Histone H3Histone H2AHMGA1a

Histone H4Histone H2A

Mre 1153BP1

hnRNPs andspicing proteins

Other mRNA-binding proteins PABPN1EWSRNA helicase ACIRPSam68FMRP

NucleolinFibrillarin

Hepatitis-δ AgHepatitis-NS3Adenovirus-L4-100EBNA1

hnRNP A1 & A2hnRNP D, G, K & UNSAP1

DNA damage response proteins

Nucleolar and ribosomalproteins

Viral proteins

Signalling proteins HMW FGF2NIP45ILF3SMAD6STATs

SmBCA150U1CSAP49

PABP1HuRHuD

PABPN1EWS

rpS2

SmBCA150SmD1 & D3Coilin

TARPP

EBNA1EBNA2

DNA Polβ

HIV-TatHIV-NCHIV-Rev

Tudor domains bind methylarginine motifs

Tud

or d

omai

ns

GAR aDMA GAR sDMA αGST

Pombe

SMN

TDRD3

SPF30

53BP1

GST

jcs.biologists.org

H2N NH2

NH

(CH2)3

C

H3N COOCH

Arginine

Type IV:

RMT2

+ AdoMet

H2N NH2

N

(CH2)3

C

H3N COOCH

CH3

MMA(δ)

+ AdoHcy

H2N N

NH

(CH2)3

C

H3N COOCH

aDMA(ω) aDMA(ω)

+ AdoHcy

CH3

CH3

Type I: PRMT1PMRT3CARM1/PRMT4PRMT6PRMT8

Type II: PRMT5PMRT7FBXO11

PRMT7Type III:

+AdoMet

+ AdoMetType I:

H2N N

NH

(CH2)3

C

H3N COOCH

MMA(ω)

+ AdoHcy

H

CH3

N N

NH

(CH2)3

C

H3N COOCH

+ AdoHcy

H

CH3

H

CH3

+ AdoMetType II:

Methylation of arginine residues

The regulation of arginine methylation

(See poster insert)

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(Wang et al., 2001), thus contributing tothe histone code. This modification onhistone H4 functions as a transcriptionalactivation mark, which could either resultin the recruitment of methyl-bindingproteins or influence the deposition ofother posttranslational marks in thevicinity. As a transcriptional coactivator,PRMT1 is recruited to promoters by anumber of different transcription factors(Bedford and Richard, 2005). The centralrole that PRMT1 plays as a regulator ofprotein function is revealed by thedisruption of this enzyme in mice.PRMT1-knockout mice die shortly afterimplantation (Pawlak et al., 2000). Thecrystal structure of PRMT1 in complexwith the reaction product (AdoHcy) and aGAR motif has been described (Zhangand Cheng, 2003).

PRMT2The first relative of PRMT1 to beidentified was PRMT2 (Katsanis et al.,1997). A novel feature of PRMT2 is thatit harbors an SH3 domain at its N-terminus (Scott et al., 1998). AlthoughPRMT2 does not have enzymaticactivity, it does function as a coactivatorfor the estrogen receptor (Qi et al.,2002). PRMT2-null mice are viable andgrossly normal (Yoshimoto et al., 2006).

PRMT3A unique property of PRMT3 is that itharbors a zinc-finger domain at its N-terminus, which is its substrate-recognition module (Tang et al., 1998).The 40S ribosomal protein S2 (rpS2) isa zinc-finger-dependent substrate ofmammalian PRMT3 (Swiercz et al.,2005). Importantly, in fission yeast thissame enzyme-substrate pair (PRMT3-rpS2) exists (Bachand and Silver, 2004),and the disruption of the prmt3 gene inthis organism results in an imbalance inthe 40S:60S free subunit ratio. Mouseembryos with a targeted disruption ofPRMT3 are small, but survive after birthand attain a normal size in adulthood. Theribosome protein rpS2 is hypomethylatedin the absence of PRMT3, whichdemonstrates that it is an in vivo PRMT3substrate (Swiercz et al., 2007).

CARM1CARM1, sometimes referred to asPRMT4, was identified in a yeast two-hybrid for proteins that associate withGRIP1, the p160 steroid receptorcoactivator (Chen et al., 1999). The

recruitment of CARM1 to promotersresults in the methylation of histone H3at Arg17 and of other coactivatorsincluding p300/CBP and AIB1 (Bedfordand Richard, 2005). CARM1-mediatedmethylation has a positive effect ontranscription. CARM1 is not only asteroid receptor coactivator but alsoenhances transcription/translation ratesin pathways responding to othertranscription factors (Bedford andRichard, 2005). In addition, CARM1methylates splicing factors and regulatesthe coupling of transcription and splicing(Cheng et al., 2007). CARM1-null micedie just after birth and are smaller thantheir wild-type littermates (Yadav et al.,2003). Cells from CARM1-null embryoshave defective estrogen receptor and NF-�B pathways. CARM1 has also beenimplicated in the epigenetic programmingof early embryos (Torres-Padilla et al.,2007). Finally, the fact that CARM1 is acoactivator for nuclear receptors makes ita likely candidate for over-expression inprostate and breast cancers. Indeed,increased expression of CARM1correlates with androgen independence inhuman prostate carcinoma (Hong et al.,2004) and CARM1 is overexpressed inbreast tumors (El Messaoudi et al., 2006).

PRMT5PRMT5 was cloned as Jak2-bindingprotein and shown to methylate histonesH2A, H3 and H4 (Branscombe et al.,2001; Pollack et al., 1999). It localizes toboth the cytoplasm and the nucleus. In thecytoplasm, PRMT5 is found in the‘methylosome’, where it is involved in themethylation of Sm proteins, whichimplicates it in snRNP biogenesis (Friesenet al., 2001). Nuclear PRMT5 associateswith regulators of transcriptionalelongation SPT4 and SPT5 (Kwak et al.,2003). Nuclear PRMT5 also formscomplexes with the hSWI/SNFchromatin-remodeling proteins BRG andBRM, where it is responsible formethylating Arg8 on histone H3 (Pal et al.,2004) and is required for muscledifferentiation (Dacwag et al., 2007).PRMT5 and H3R8 methylation levels areelevated in lymphoid cancer cells (Pal etal., 2007). A general note of cautionshould be added here: the Reinberg grouphave found that �FLAG M2-agaroseenriches for PRMT5 activity (Nishiokaand Reinberg, 2003); thus many affinity-purified FLAG-tagged complexes are‘contaminated’ with PRMT5.

PRMT6PRMT6 is restricted to the nucleus andit has the ability to methylate itself(Frankel et al., 2002). Like PRMT1,PRMT6 methylates a GAR motif.However, it displays unique substratespecificity – it methylates histones H3and H4 in vitro, whereas PRMT1 onlymethylates histone H4 (Lee et al., 2004).DNA polymerase � was found to form acomplex with PRMT6. Methylation ofPol � by PRMT6 strongly stimulatesDNA polymerase activity (El-Andaloussi et al., 2006). Thus, PRMT6plays a role regulating DNA baseexcision repair. Finally, PRMT6 has alsobeen shown to methylate a number ofHIV proteins (Invernizzi et al., 2007).

PRMT7PRMT7 was first identified in a geneticscreen for susceptibility to chemo -therapeutic cytotoxicity (Gros et al.,2003). It is one of two PRMTs that harbortwo putative AdoMet-binding motifs(Miranda et al., 2004). It has a strongpropensity to catalyze the formation ofMMA but not DMA on a fibrillarin-derived peptide substrate (Miranda et al.,2004). Miranda et al. thus classifiedPRMT7 as a type III enzyme. Using adifferent peptide substrate, Lee et al.showed that PRMT7 catalyzes theformation of sDMA, consequentlyclassifying it as a type II enzyme (Lee etal., 2005b). It is possible that distinctsubstrates are methylated in differentfashions by this enzyme. A study thatfocused on identifying loci thatimpart susceptibility to drug-inducednephropathy has implicated PRMT7 as acandidate (Zheng et al., 2005). Also,PRMT7 plays a role in male germlineimprinted gene methylation through itsinteraction with CTCFL (a protein thatassociates with the imprinting controlregion) and subsequent methylation ofhistone 4 Arg3 (Jelinic et al., 2006).

PRMT8PRMT8 was identified through its highdegree of sequence identity to PRMT1(Lee et al., 2005a). PRMT8 has a uniqueN-terminus that harbors a myristoylationmotif that facilitates its association withthe plasma membrane. It is largelyrestricted to the brain.

PRMT9 (4q31)PRMT9 (4q31) was first identified at thesame time that PRMT8 was described

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(Lee et al., 2005a). In common withPRMT7, it harbors two putativeAdoMet-binding motifs. In addition, atits N-terminus PRMT9 has a TPRrepeat, which may be a protein-proteininteraction module (Bedford, 2006).

FBXO11FBXO11, also referred to as PRMT9(2p16.3), was identified as a potentialPRMT because it has regions thatdisplay weak sequence similarity to theI, post-I, II and III amino acid sequencemotifs (Cook et al., 2006). Unlike otherPRMTs, it does not harbor a THW loop;however, FLAG-tagged hFBXO11 hasbeen reported to have type II activity(Cook et al., 2006), but HA-taggedhFBXO11 and its C. elegans ortholog(DRE-1) have been reported not to havePRMT activity (Fielenbach et al., 2007).

PRMT substratesProteins that harbor GAR motifs areoften targets for PRMTs, althoughCARM1 is an exception and cannotmethylate a GAR motif. Recentadvances in mass spectrometry meanthat more and more isolated methylationsites that are not within GAR motifs arebeing identified. In addition, bothCARM1 and PRMT5 can also methylatePGM motifs (Cheng et al., 2007).PGM motifs are proline-, glycine-,methionine-, arginine-rich patches thatare found in a number of splicing factors(Bedford et al., 1998). PRMT substrateshave been extensively reviewed recently(McBride, 2006; Pahlich et al., 2006).

Methylation regulates protein-protein interactionsArginine methylation facilitates theinteraction of GAR and PGM motifswith Tudor domains. The symmetricdimethylation of SmB by PRMT5 isrequired for its interaction with theTudor domains of SMN, SPF30 andTDRD3 (Cote and Richard, 2005). Theasymmetric dimethylation of CA150 byCARM1 also provides a docking site forthe Tudor domain of SMN (Cheng et al.,2007). Thus, motifs harboring eitheraDMA or sDMA residues bind a subsetof Tudor-domain-containing proteins. Itis likely that a conserved aromatic ‘cage’in Tudor domains is the methyl-bindingpocket (Sprangers et al., 2003).

Arginine methylation can also act as anegative regulator of protein-protein

interactions. For example, themethylation of arginine residues adjacentto a proline-rich motif can block bindingto SH3, but not WW, domains (Bedfordet al., 2000). A second example is theCARM1-mediated modification of theGRIP1-binding domain of p300 (Leeet al., 2005c). Finally, histone H3methylation at Lys4 provides a dockingsite for the double chromodomains ofCHD1 (chromo-helicase/ATPase DNA-binding protein 1). The histone H3 Arg2site is reported to be methylatedby CARM1, and this methylationtogether with Lys4 methylation(H3K4me3R2me2a) decreases thebinding affinity fourfold relative tohistone H3 Lys4 methylation alone(Flanagan et al., 2005).

Regulation of argininemethylationPRMT-binding proteins can regulate theactivity of PRMTs. They can inhibit,activate, or change the substratespecificity of PRMTs. The relatedproteins BTG1 and TIS2/BTG2 bind toPRMT1 and stimulate its activitytowards selected substrates (Lin et al.,1996). The BTG1-binding proteinhCAF1 also regulates PRMT1 activity(Robin-Lespinasse et al., 2007). Bindingof the tumor suppressor DAL-1 toPRMT3 acts as an inhibitor of enzymeactivity, both in vitro and in cell lines(Singh et al., 2004). CARM1 is found ina complex of at least 10 proteins calledthe nucleosomal methylation activatorcomplex (NUMAC) (Xu et al., 2004).CARM1 within NUMAC acquires theability to methylate nucleosomal histoneH3, whereas recombinant CARM1preferentially methylates free histoneH3. PRMT5 forms complexes with thehSWI/SNF chromatin remodelers BRGand BRM, and this association enhancesPRMT5 methyltransferase activity (Palet al., 2004). The binding of CTCFL toPRMT7 has also been reported to elevatethe activity of this PRMT (Jelinic et al.,2006).

Arginine residues within proteins canbe converted to citrulline bydeimination. A major group ofdeiminated proteins are the corehistones H2A, H3 and H4 (Nakashimaet al., 2002). The peptidyl argininedeiminases (PADs) can blockmethylation on an arginine residue byconverting it to citrulline (Cuthbert et

al., 2004; Wang et al., 2004). PADscatalyze the deimination of arginine,but not MMA or DMA, to citrulline(Raijmakers et al., 2007). Thus,peptidyl arginine deiminases are notdemethylases. However, these enzymesmay carry out a preemptive strike onkey sites of arginine methylation,thereby preventing subsequentmethylation. The first evidence thatPRMTs themselves are regulated byposttranslational events was recentlydescribed (Higashimoto et al., 2007). Inthis case, the phosphorylation ofCARM1 results in a decrease in PRMTactivity. There are no reported argininedemethylases and this topic is an activearea of research.

Thank you to Steven Clarke for his comments on thisreview. M.T.B. is supported by NIH grant DK62248.

Note added in ProofThe first arginine demethylase has beenidentified very recently (Chang et al.,2007). This protein, JMJD6, is aJumonji-domain-containing protein. Inaddition, PRMT6 has recently beenshown to methylate H3R2 (Guccione etal., 2007).

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