on wd40 proteins propelling our knowledge of transcriptional control?

7/27/2019 On WD40 Proteins Propelling Our Knowledge of Transcriptional Control?

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.ladesbscece.cm Epgeecs 815

Epgeecs 7:8, 815822; Augus 2012; 2012 Lades Bscece

Point-o-ViEw Point-o-ViEw

Keywords: arginine methylation, WD40,chromatin, histone modiications,WDR5, MLL

Submitted: 05/03/12

Revised: 06/11/12

Accepted: 06/15/12

http://dx.doi.org/10.4161/epi.21140

*Correspondence to: Marina Mapelli

and Ernesto Guccione;

Email: [email protected]

and [email protected]

Adirect eect o post-translationalmodifcations (PTMs) on nucleo-somes is the ormation o a dynamic plat-orm able to assemble the transcriptional

machinery and to recruit chromatinmodifers. The histone code hypothesissuggests that histone PTMs can act asbinding sites or chromatin readers andeector proteins, such as the bromo-domains, that selectively interact withacetylated lysines, or the royal amilyand the PHD fnger domains, which areable to recognize methylated argininesand lysines. In this review we will dis-cuss recent data describing the unctiono WD40 proteins as a new class o his-

tone readers, with particular emphasison the ones able to recognize methylatedarginine and lysine residues. We willdiscuss how WDR5, a classical seven-bladed WD40 propeller, is able to bind

with similar afnities both the catalyticsubunit o the Trithorax-like complexes,and the histone H3 tail either unmodi-fed or symmetrically dimethylated onarginine 2 (H3R2me2s). Furthermore,

we will speculate on how these mutuallyexclusive interactions o WDR5 may playa role in mediating dierent degrees o

H3K4 methylations at both promotersand distal regulatory sites. Finally, we

will summarize recent literature eluci-dating how other WD40 proteins such asNURF55, EED and LRWD1 recognizemethylated histone tails, highlightingsimilarities and dierences among them.

On WD40 proteinsPropelling our knowledge o transcriptional control?

Valentina Migliori,1,2 Marina Mapelli3,* and Ernesto Guccione1,2,*1Institute o Molecular and Cell Biology; Singapore, Singapore; 2Department o Biochemistry; Yong Loo Lin School o Medicine;

National University o Singapore; Singapore, Singapore; 3Department o Experimental Oncology; European Institute o Oncology; Milano, Italy

WD40-Containing Proteinsare Adaptor Proteins Mediating

Protein-Protein Interactions

WD40 repeats (also known as WDrepeats) are 4060 amino acid motis thatpreerentially end with a tryptophan andan aspartic acid (WD). They are highlyconserved rom bacteria to mammals, andare oten ound as part o multisubunitcomplexes, where they play a role in medi-ating protein-protein interactions. Therst WD40 containing protein was identi-ed as part o the heterotrimeric G proteintransducin complex.1 The crystal structureo the subunit o the complex showed

the characteristic seven-blade

-propellerold, with a central cavity (Fig. 1A and B),and each blade comprising a our-strandedanti-parallel -sheet (Fig. 1C).2-4 It waslater shown that propeller can be assem-bled with a number o repeats varyingbetween 4 and 16 (SMART:SM00320;I N T E R P R O : I P R 0 0 1 6 8 0 ; P F A M :PF00400;PROSITE:PS00678).

As highl ighted by the crysta llographicstructures determined to date, WD40domain proteins have several suracesor the interaction with multiple bind-

ing partners, and it is no surprise thatthey are crucial or maintaining theintegrity o the complexes that they arepart o. They serve as interaction hubsand are associated with a wide varietyo physiological pathways such as vesi-cle biogenesis,5 cytokinesis,6 control o


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816 Epgeecs Vlume 7 issue 8

o WDR5 toward unmodied H3 rangingrom 3.3 to 35M (K

D). Moreover, despite

an increased protein stability o WDR5bound to H3K4me2 over unmodied H3,as measured by dierential static lightscattering,24 none o the groups detectedthe increase in anity toward K4 methyl-ated peptides that was initially reported.21Recently, it was shown that WDR5 bindsH3 peptides symmetrically dimethylatedon arginine (H3R2me2s) with a higheranity, likely due to a reorganization o

the water-mediated interaction networkwithin the central channel. SpecicallyH3R2me2s is hydrogen-bonded to onlyone water molecule, as opposed to twowaters bridging the interaction o WDR5with unmodied H3R2me.14 The crystal-lographic structure o WDR5 in complexwith H3R2me2s revealed a marginal shito the methylated, hydrophobic guanidin-ium group o H3R2 away rom the singlewater molecule present in the direct ion oa hydrophobic pocket contributed by thePhe219 o WDR5 (Fig. 2A). Phe219 is

thus an important determinant o the highanity interaction between WDR5 andH3R2me2s. Following this line o reason-ing, mutation o Phe219 into more hydro-philic residues (WDR5-F219H) reducesthe binding anity between H3R2me2sand WDR5 rom a K

Do 0.1 M to

0.21.1 M, without severely aectingthe binding to the unmodied H3R2me0(KD o 5.6 1.5 M to 7.0 2.0 M)(Migliori and Guccione, unpublished).

methyltranserases (PRMTs) and sequen-tially asymmetrically (by type I PRMTs)or symmetrically (by type II PRMTs)dimethylated.15 Only a ew proteins havebeen shown to interact specically withmethylated arginines on histones. Forexample, TDRD3 is a transcriptionalco-activator which directly interactswith H3R17me2a16 (where a standsor asymmetric), and the ADD domaino DNMT3A could possibly bind toH4R3me2s (where s reers to symmet-

ric), though this is still controversial.

17,18

Recently, it has been shown that themethylation on H3R2 critically aectsthe binding o the transcriptional co-activator protein WDR5 to histone H3.Specically, the symmetric dimethylationleads to WDR5 recruitment,14 while theasymmetric dimethylation excludes itsbinding.13,19,20

Wysocka and coworkers showed thatWDR5 could bind to unmodied his-tone H3, and that the anity was stron-ger between WDR5 and a dimethylated

H3K4 peptide (H3K4me2).21

Three laterstudies independently were able to deter-mine the structure o WDR5, whicholds as a classical seven-blade -propeller(Fig. 2A),22-24 bound to H3. Analysis othe structure revealed that Ala1, Arg2 andThr3 o H3 are important or the specic-ity o binding, and that the side chain oArg2 inserts into the central channel o the-propeller.22-24 Depending on the assayused, the three groups reported an anity

protein stability,7 RNA processing,8 con-trol o replication9,10 and transcriptionalregulation.11-14

In terms o transcriptional regulation,proteins containing WD-domains, suchas EED, LRWD1, WDR77, RbBP4/7 andthe Drosophila homolog NURF55, havebeen shown to mediate the localizationo chromatin modiers to specic siteson the genome by directly binding to his-tones and their methylated tails.

Here, we will summarize recent litera-

ture elucidating how WDR5, EED andNURF55 bind to histone tails, highlight-ing similarities and dierences betweenthem.

WD40 Containing Proteinsas Chromatin Readers

WDR5. Unlike phosphorylation or acety-lation, methylation o histones does notchange the overall charge o the modi-ed amino acids, but it does render thembulkier and more hydrophobic. It is thus

thought that methylation at specic sites,either on the histone globular domain oron the tails, can lead to either transcrip-tional activation or repression, dependingon downstream proteins recognizing thespecic methylation event. Methylationcan occur either on lysines, which canbe mono-, di- or trimethylated by lysinemethyltranserases (KMTs) or on argi-nines, which can be monomethylatedby class I, II and III protein arginine

Figure 1. tplgy wD40 prpellers. (A ad B) Rbb dagrams a seveblade wD40 prpeller veed rm he sde ad rm he p.

the blades are rgazed sequeally, ad pack each her cuerclckse arud a ceral chael. the clsure he rglke srucure s

acheved blade 7 by he crbu he srad 7ddervg rm he nermal resdues he dma. (C) Each blade he prpeller c

sss a shee rmed by ur aparallel srads, hch are deed a-b-c-dsarg rm he erms srad he ms perpheral. nably,

he srad d each blade crrespds he nermal srad he subseque wD40 repea.


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How is it possible to reconcile thesebiochemical data with the high degree oco-localization observed in vivo betweenH3R2me2s and methylated H3K4?14,30The presence o H3K4me1 at distalregulatory sites has been long observedby several groups,31-33 but the mecha-nism by which H3K4me1 is preeren-tially catalyzed over H3K4me2/3 is stilllargely unknown. One possibility is the

The topology o the WDR5:MLLWin inter-action is reminiscent o what observed orWDR5:H3R2 (Fig. 2B).

Very importantly there seem to be adirect competition between H3 and theWin moti peptides in binding to WDR5,implying that the Win moti acts as dosedependent inhibitor o complex orma-tion and catalytic activity toward H3K4methylation.29

Intriguingly, works by other groups25-27have shown that the binding pocket oWDR5, which interacts with H3R2me2s,can also interact with the SET domaino MLL1 with comparable anity, viathe so called Win (WDR5 interacting)moti.14,25-27 This association is not specicor MLL1, as initially thought, and it isindeed conserved among all SET domainmembers: MLL24, SET1A and SET1B.28

Figure 2. Srucural rgaza wD40dmas cmplex h hse als ad her lgads. (A) Srucure wDR5 (clred lgh blue)

cmplex h he nermal ragme hse H3 ( yell ballsadscks) symmercally dmehylaed Arg2 (PDB d 4A7J). the H3 pepde

les he p surace he prpeller serg he Arg2 sde cha he ceral chael, beee cserved Phe armac rgs. A hebm he cav y, he erac s ur her sablzed by hydrphbc eracs h Phe219 ad by a aermedaed hydrge bd Ser175.

i hs cgura, he sde cha Lys4 ps aay rm he prpeller. (B) the MLL2 w pepde ecmpassg Arg5065 (sh pk) bds

wDR5 much he same ay as he hse H3 nermus, mplyg ha he lgads are muually exclusve eracrs wDR5 (PDB d 3UVK).

(C) Archecure he EED wD40 prpeller (dsplayed gree) cmplex h hse H3 rmeyhylaed Lys27 (PDB d 3iiw). the mehylaed

H3K27 sde cha s dcked he prpeller surace by hydrphbc eracs crbued by Phe97, tyr148 ad tyr365. the presece EED

bulky resdues such as tyr308 ad trp364 resrcs he bdg hse pepdes cdg r small resdues ps 2 rm he mehylaed Lys.

(D) tplgy nUR55 (clred llac) bud hse H4 (PDB d 2XYi). the hse H4 pepde lds as a helx ha s a grve he

laeral surace he prpeller. the amphpahc characer he helx h psvely charged resdues he le sde ad hydrphbc sde chas

he ppse, maches he chemcal evrme he prpellers grve (le pael). (E) the PRC2 subu Su(z)12 (sh red) recgzes he

same laeral grve he nUR55 prpeller ccuped by hse H4 (PDB d2YB8). () Srucure nUR55 cmplex he nermus hse

H3 (PDB d 2YBA). the H3 pepde rus he p he prpeller a exeded crma, serg he Arg2 sde cha beee tyr185 ad

Phe325. ths gemery s remsce he cmplex h wDR5, alhugh Arg2 des g as deep he ceral chael, ad addal plar

eracs crbued by Glu130nUR55, Glu183 nUR55 ad As132 nUR55 achr he Lys4H3 sde cha he prpeller surace.


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at enhancer sites distant rom TSSs14

(Fig. 3B). These hypotheses are provoca-tive, but it must be said that the mecha-nistic details o the WRAD mediatedmethylation are still largely missing and itis still unclear whether a dual catalytic site(one on MLL and the second on WRAD)is used toward an ecient tri-methylationo the substrates. Moreover, Takahashiand colleagues have recently shown thatthe reconstituted yeast WRAD complexdoes not have a substantial HMT activity.

(WR AD) sub-complex could be recruited

to chromatin via the high anity inter-action between WDR5 and H3R2me2s,in the absence o MLL/SET recruitment.Interestingly, this sub-complex has beenproposed to have direct H3K4 monometh-ylation activity, which is dependent onthe ability o the ASH2L-SPRY domainto bind the coactor S-adenosyl methio-nine (SAM).35,36 The WRAD enzymaticactivity would t with the observed co-localization o H3R2me2s and H3K4me1

recruitment o histone demethylases that

can demethylate H3K4me2/3 (KDMs)34

or, alternatively, enzymes other thanMLL could be involved in promotingH3K4 monomethylation (Fig. 3A). Atthose distal regulatory sites marked byH3R2me2s, the competitive binding oWDR5 to both H3R2me2s and the SETcatalytic subunit o the Lys4-methylatingcomplexes might have a regulatory unc-tion on the latter. The rst possibility isthat the WDR5/ASH2L/RBBP5/DPY30

Figure 3. Regula he MLL/SEt cmplexes a dsal regulary ses (ehacers) ad a prmers. (A) H3K4 s efcely d ad rmehylaed

(H3K4me2/3) vv by MLL/SEt cmplexes. A dsal regulary ses H3K4me1 s mre abudaly deeced, eher because a csa demehyl

a by Jumjcag ezymes r by LSD1/2 (KDMs) r because alerave ezymes (SEtx) drecly mmehylae H3K4. (B) i he absece

he MLL/SEt caalyc subu, he wRAD cmplex culd peally mmehylae H3K4me1. Aleravely, he cmpe beee wDR5, H3 ad

he w M pepde MLL/SEt pres culd lead reduced efcecy H3K4 rmehyla ad a cseque ehaced mmehyla

a hese ses. (C) Acve prmers ha are erched r H3R2me2s ll recru he MLL/SEt cmplex rmehylae H3K4 (H3K4me3). (D) whe

he 1 uclesme s mehylaed H3R2 (H3R2me2s) wDR5 ll bd h hgh afy, ms lkely he absece he caalyc MLL/SEt subu.

i rder be rmehylaed H3K4, he hse al ll he raslcae he caalyc pcke he MLL/SEt (crmaal chage). (E) wDR5

bdg H3 culd be urelaed he wRAD ad MLL/SEt cmplexes. wDR5 s par he AtAC, he Mo ad he CHD8 remdeler cmplex amg

pssbly hers.


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the binding o large or charged aminoacids, specically at position-2, that typi-cally fank activation marks on histones.This could provide a molecular explana-tion or the evidence that EED binds toH3K27me3 and H3K9me3 (ARKS),but not to H3K4me3 (RTKQ) (Fig. 2C)

While EED has only been observed tobind H3K27me3 in vivo, in vitro it bindsto most o the repressive marks, such asH3K9me3 or H4K20me3, with an an-ity that decreases with the degree o meth-ylation (or example, H3K27me3 > me2> me1). This poor specicity observed invitro could be explained by the topologyo the interaction between EED and theH3K27 histone marks that occur only onthe top surace o the -propeller and notin the central channel (Fig. 2C). Instead,in the case o WDR5, the prominent ea-

ture o the association o the H3 tail withthe -propeller is the insertion o the Arg2side chain into the central cavity, where thepresence o two phenylalanines avors theormation o a specic hydrophobic inter-action with H3R2me2s14 (Fig. 2A). As aresult, the interaction between WDR5and H3R2me2s appears to be extremelyspecic. In sharp contrast to EED thatcan bind several dierentially methylatedresidues on histone H3 in vitro, WDR5has not been observed to interact with any

other symmetrically di-methylated argi-nines on histones (Migliori and Guccione,unpublished).

NURF55 and RbBP4/7. BesidesEED, the PRC2 complex contains a sec-ond WD40 protein termed NURF55 inDrosophila and RBBP4/7 in humans.This seven-blade -propeller was origi-nally identied as an interacting part-ner o the Retinoblastoma protein.49Subsequently it was co-puried with theHAT1 acetyltranserase complex50 andseveral co-repressor complexes, including

PRC2,51

NURD52

and CAF1.53

WhileNURF55 has been demonstrated to bindboth H3 and H4,54,55 the precise mecha-nism by which the binding o this multi-unctional chromatin reader is modulatedby the crosstalk among histone modica-tions was only recently described.

The crystal structure o NURF55bound to histone H4 revealed that thebinding occurs with the rst helix o thehistone old, a region normally buried

modication that would be predicted todestroy the binding, as observed in thecase o H3R2me2a/me1 and WDR5.13,20,22More experiments are needed to clariythis point.

It is worth mentioning that the initialproposed model o WDR5 as the protein

responsible to present the histone H3 tailto the MLL complex or methylation,is probably not accurate.21,40,41 On thecontrary, it has been reported that theN-terminal o the histone tail has to beree to allow methylation by MLL,37,42while WDR5 plays a role in maintainingthe integrity o the complex.

An alternate role or the observed bind-ing o WDR5 to histone H3 has to nallybe considered. WDR5 is part o severalother complexes, or example the ATACcomplex43 and the MOF complex,44 which

possess acetyltranserase activity, andcould in turn act to promote H3K4me3,45or the CHD8-containing chromatinremodeling complex,46 which could besimilarly important to promote acces-sibility or urther histone modications(Fig. 3E).

EED. The interplay between WDR5,H3 (either unmodied or symmetricallydimethylated on R2) and the other com-ponents o the SET complexes is reminis-cent o another important WD40 domain

protein: EED. EED, together with EZH2and SU(z)12, orm the PRC2 complex,a transcriptional co-repressor complexwhose activity depends on its ability totrimethylate H3K27. While EZH2 isthe catalytic subunit o the PRC2 com-plex, EED binds directly to H3K27me3through its C-terminal domain, leadingto the allosteric activation o the meth-yltranserase activity o PRC2 and, assuch, to the propagation o the repres-sive mark.47,48 Similarly, H3R2me2s mayavor H3K4 methylation by its interaction

with WDR5 (Fig. 3D). This interactiondisplaces the Win moti rom the WDR5binding clet, and could cause an allo-steric change in the complex, leading toits activation or avoring its processivity.The structure o EED in complex withH3K27me3 shows that the interactionoccurs through a hydrophobic/aromaticcavity ormed mainly by three residues:Phe97, Tyr148 and Tyr365. The peculiar-ity o this cage is that it is able to prevent

Indeed, when they use the WRAD com-plex, less than 1% o H3K4me1 and noH3K4me23 were detected in theirmethylation assays, much less than whatobserved with the wt Set1/COMPASS orMLL/COMPASS-like complexes.37 Thesediscrepancies could be due to the dierent

protocols used to puriy the complex sub-units or the quality o the substrate, thuswe reckon additional experiments will benecessary to clariy the issue.

A second role or the presence oH3R2me2s at distal regulatory sites couldbe to avor the dissociation o the MLL/SET complex itsel rom the WRAD, bydirectly competing or the Win moti.This would lead to a preerential mono-over trimethylation o H3K4 (H3K4me1> H3K4me3) (Fig. 3B).

At promoters H3K4me3 is typica lly

enriched over H3K4me138,39 (Fig. 3C).It is possible that at the subset o pro-moters marked by both H3K4me3 andH3R2me2s, the topology o the inter-actions among subunits o the WDR5/Ash2/Rbbp5/DPY30 sub complex is rear-ranged by the direct binding o the SETcatalytic subunit to WDR5, via the Winmoti. I so, the WRAD complex could berecruited rst by the high anity interac-tion with H3R2me2s, and then undergo aconormational change leading to assem-

bly o the ull complex that trimethyl-ates histone H3 (Fig. 3D). Detailed timecourse studies will have to be perormedin order to clariy whether this is the case.

Interestingly, a recent study onH3R2me2s both in yeast and eukaryoticcells reports a much higher degree o over-lap between H3R2me2s and H3K4me3 atpromoters. By taking advantage o yeastgenetics, the authors urther prove thatthe interdependency between H3R2me2sand H3K4me3 is mutual, since the argi-nine methylation mark is not present in a

SET1 mutant background.30

Although no ormal proo has beenprovided to date, it is possible that theWin moti o the MLL proteins can alsobe symmetrically methylated on the argi-nine required or the binding to WDR5,and that this methylation could enableMLL to better compete with H3R2me2sor binding to WDR5. Alternatively,the Win moti could possibly be mono-or asymmetrically dimethylated, a


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However, the authors ail to explain themechanisms by which the WD40 motissimultaneously interact with H3K9me3,ORC and other possible co-repressors tostabilize heterochromatin in cis.62 Thiswill be an interesting aspect to addresswith both biochemical and structural biol-

ogy studies.

WD40 Domains

as Flexible Scaffoldsfor Intracellular Interactions

A recent report by Wang and colleaguesidentied HOTTIP, a long non-codingRNA transcribed rom the 5' o the HOXAlocus, as a direct interactor o WDR5. Invivo, HOTTIP has been shown to coor-dinate the activation o several HOXAgenes and its binding to WDR5 targets

the MLL complex activity to all genes inthe HOXA cluster.63

WDR5 is also the rst member o theTrithorax complex to be shown to directlyinteract with Oct4 and to regulate sel-renewal in mouse embryonic stem cells.64The authors observed a strong correla-tion between WDR5 and Oct4 bindingto chromatin on a genome-wide scale.Moreover, they proved that WDR5 isrequired in the initial phase o somatic cellreprogramming to iPS cells and propose

a model in which Oct4 rst binds andpromotes WDR5 expression in somaticcells, then interacts with WDR5 and con-ers DNA specicity to the WDR5/MLLcomplex. This re-establishes H3K4me3on sel-renewal genes such as Nanog orPou51, promoting subsequent strongbinding o Oct4 to these promoters anddirecting a robust transcriptional activa-tion o the pluripotency network.64

To conclude, WD40-containing pro-teins are versatile proteins, which cansimultaneously mediate interactions

between histones, protein- and RNA-partners, thus integrating complex signal-ing pathways and ultimately controllinggene transcription.

Acknowledgments

We are grateul to Cheryl Mei-Yi Koh orcritically reading the manuscript.

residue does not impair binding.56 This isin line with more recent data showing thatthe opposite symmetricity (H3R2me2s)has a negative eect on this interaction.14

WDR77. The coactor WDR77, alsocalled Mep50, is another WD40 protein,which directly interacts with histones.

WDR77 binds specically to histoneH2A, most likely avoring the specicmethylation o H2AR3 by PRMT5.58The exact surace o interaction and howWDR77 stimulates this methylationevent is however, still unknown. Solvingthe crystal structure o PRMT5/WDR77in combination with H2A will proveextremely interesting and provide urtherunderstanding into the role o this WD40protein in aiding PRMT5 activity.

It is also important to note thatPRMT5 methylates histones both in the

nucleus and in the cytoplasm. Specicallythe symmetrical dimethyation o H2AR3seems to occur in the cytoplasm, contribut-ing to the repression o pro-dierentiationgenes in embryonic stem cells.59 Whetherthis holds true or the other histone meth-ylation events catalyzed by PRMT5, suchas H3R2me2s or H3R8me2s, remains tobe addressed.

LRWD1. In two recent proteomicscreens, LRWD1, another WD40repeat-containing protein, was identi-

ed to interact with repressive trimethylmarks (H3K9me3, H3K27me3 andH4K20me3) and with the ORC com-plex.60,61 Further studies have shownthat LRWD1 stabilizes ORC binding tochromatin, specically heterochromatin.9While the ability o LRWD1 to bind het-erochromatin was accurately described bymultiple groups, none addressed whetherthis interaction occurred directly or indi-rectly. A more recent study proved thatLRWD1 is recruited to pericentric het-erochromatin by its direct binding to

H3K9me3. The localization o the WD40protein is not altered in cells lackingH4K20me3 (Suv420h1h2-/-), while it iscompromised in cells lacking H3K9me3(Suv39h1h2-/-). Functionally, this inter-action helps to maintain heterochromatinsilencing, as Lrwd1 knockdown results inailure to silence the major satellite repeats.

in the nucleosome structure (Fig. 2D).25Consistently, mutations that disruptedsuch interactions led specically to the losso HAT1 acetyltranserase activity, whichis directed toward newly synthetized andnon-nucleosomal H4. Unlike the bindingbetween WDR5 and histone H3, which

occurs deep in the central cavity o theWD40 propeller, NURF55 interacts withH4 on the side surace o the protein. Thebinding surace is hydrophobic on oneside, and negatively charged on the other,thus perectly matching the H4-helix,which has alternating hydrophobic andpositively-charged amino acids (Fig. 2D).The extensive hydrogen bond networkthat stabilizes the binding is unique to thesurace o this -propeller, and is absentin WDR5 and other members o the am-ily. RBBP4/7 is also part o the NURF

complex, and it remains to be addressedwhether the interaction surace on H4 ismade accessible during the remodelingprocess by the ISWI-containing ATP-dependent chromatin-remodeling com-plex. By determining the crystallographicstructure o NURF55 bound to H3, a morerecent publication reconciled the bindingdata with the direct activity o NURF55-containing complexes on chromatin.56 Theauthors show that in the context o thePRC2 complex, NURF55 is able to bind

to both Su(z)12, which binds in the samebinding pocket as the H4 peptide (Fig.2E), and to H3, which instead binds onthe top-fat surace o the -propeller (Fig.2F). Unlike WDR5, the arginine at posi-tion 2 does not interact with residues deepin the central cavity, but is nonethelessvery important in recognizing NURF55,together with H3K4 whose side chain isdocked on the propeller surace by polarinteractions with negatively charged resi-dues o NURF55. Consistently, methyla-tion on H3K4 impairs NURF55/Su(z)12

binding.56,57

More specically, H3K4me3methylation on nucleosomes reduces thecatalytic turnover o PRC2, resulting inan overall reduction in H3K27 meth-ylation. Interestingly, despite an involve-ment o H3R2 in binding to the suraceo NURF, the presence o the asymmet-ric dimethylation (H3R2me2a) o this


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on wd40 proteins propelling our knowledge of transcriptional control?

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