Abstract
Protein post-translational modifications (PTMs) in eukaryotic cells play important roles in the regulation of functionalities of the proteome and in the tempo-spatial control of cellular processes. Most PTMs enact their regulatory functions by affecting the biochemical properties of substrate proteins such as altering structural conformation, protein–protein interaction, and protein–nucleic acid interaction. Amid various PTMs, arginine methylation is widespread in all eukaryotic organisms, from yeasts to humans. Arginine methylation in many situations can drastically or subtly affect the interactions of substrate proteins with their partnering proteins or nucleic acids, thus impacting major cellular programs. Recently, arginine methylation has become an important regulator of the formation of membrane-less organelles inside cells, a phenomenon of liquid–liquid phase separation (LLPS), through altering π-cation interactions. Another unique feature of arginine methylation lies in its impact on cellular physiology through its downstream amino acid product, asymmetric dimethylarginine (ADMA). Accumulation of ADMA in cells and in the circulating bloodstream is connected with endothelial dysfunction and a variety of syndromes of cardiovascular diseases. Herein, we review the current knowledge and understanding of protein arginine methylation in regards to its canonical function in direct protein regulation, as well as the biological axis of protein arginine methylation and ADMA biology.
Highlights
Higher-order organisms generally share conserved or similar chemical mechanisms of bimolecular synthesis and metabolism in comparison to lower-order organisms such as prokaryotes
Arginine methylation in mammalian cells is catalyzed by the class I, S-adenosyl-l-methionine (SAM or AdoMet)-dependent methyltransferases named protein N-arginine methyltransferases (PRMTs) [12,13,14,15,16]
WMicTita7hliilnsytthhinee doPnRulMyceTkdnfoakwmnniloytcy, kPpdRe MoIIIwTP1nRaMnodfTPPinRRMmMaTmT5 1maraaelntiahdne PRMT5 in mouse emmbarjoyronpliacyefirbs rionbvolalvsetdceinllscastiaglynziifingcatnhtelyburelkduofceasrgRinminee2ma eltehvyelaltsiobnyin~5m8a%mmanaldianRmceells2.s levels by ~95%, respCehcetmivicealyly [1in3d–u1c5ed]. knockdown of PRMT1 and PRMT5 in mouse embryonic fibroblast cells significantly reduces Rme2a levels by ~58% and Rme2s levels by ~95%, respectively [13,14,15]
Summary
Higher-order organisms (e.g., mammals) generally share conserved or similar chemical mechanisms of bimolecular synthesis and metabolism in comparison to lower-order organisms such as prokaryotes. Sophisticated regulatory mechanisms and networks are present in eukaryotic cells to control or modulate cellular programs for development, differentiation, survival, and adaptation. Such complex mechanisms of regulation include gene fusion/translocation, epigenetics, RNA splicing, protein-protein interaction, protein-nucleic acid association, and post-translational modifications (PTMs) of proteins. A myriad of post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, acetylation, methylation) allow for ON/OFF-switching or fine tuning of protein-controlled cellular processes in response to intracellular and extracellular signals. Arginine residues can be methylated on the guanidinium nitrogen atoms in three different states—NG-monomethylarginine (Rme1), asymmetric NG,NG-dimethylarginine (Rme2a), and symmInet.tJr. Micol.NSciG. Eart/kidney tissue hydrolysates showed that Rme2a level is higher than Rme2s by 5–6 fold [4] Reported r2eosfu18lts on the stoichiometric abundance of different methylation states, varying at different degrees, generally sstuatpesAp—rogNritnG-inmtheoanrteosmmideuothensyolcamarngeinbtiehnyemlea(ttRheymdlaet1ae)d,rgoiannsyitnmheemgeiustraicmnidoNinrGei,uNmaGb-dnuiimtnroedtghaeynnltaartgtohimnaisnneind(itRhmmreeeet2hday)if,flearatenenddt arginine sites in prosytemimnse.triDc ilNwG,orNth’G-adnimdetBhayrlasrygtinei-nLeov(Remjoey2sa) n(aFliyguzreed 1t)he[3n,6u–8m].beRrepoofrtaerdgirneisnuletsmoenthtyhleation sites in the Phosstpoihchoiosmitetrdicataabbunadsaenbceyomf deitfhfeyrelnsttmateeth, yalnatdionfosutanteds, tahltahtouagrhgivnairnyeingmaetthdiyfflearteinotndepgrreedso, minantly exists in thgeenRermalley1sufpopromrt t(h~at8m4%on)o,maenthdyltahteedraergsitn(in~e1i6s %mo)raeraebudnidmanettthhyanladrigmienthinyleat(eidnacrlguindiinnegsitResme2a and Rme2s) [9]iP.nhGpousropotheoeinstista.elD.dialpwtaeobrraftosherambnydemdBeaitrmhsyymltes-utLanotevo,epajonryedcafionpuailntydaztetidhoantthaearnnguidnmipnbereomrtoeeftohamyrglaiicntiioannne pamrlyeedtshoiysmlaaitnnioadnntfslyoitueesxniisdntstthhineat Rme is 3–4 fold mtohreeRambeu nfodrman(t~8t4h%a)n, aRndmteh2eareisnt (H~1C6%T)1a1r6e dciemllesth[y1l0ar]g. iInninteh(iencTlruydpinagnRosmoem2aa abnrducRemi,ei2ts)w[9a]s. reported that methyGluaorgetinali.npeercfoormmepdrimsemduanpopprreocixpitmatiaotnealynd1p0r%oteoofmtichaenpalryositseaonmd feou[1n1d]t,hatnRdmteh1eisp3r–o4 tfeooldmic study revealed thmaotrethabeunnduamntbthearnoRfmpee2pa tiindHe CfrTa11g6mceelnlsts[10c]o. nIntatihneinTrgypRanmoseom1aisbru8c.e2i,-fiot lwdasorfepdoirmteedththyaltarginines, and the abmrueventedhaylaelnadrcgtheinaotintfheRecmnoumemp2braeisriesodf2pa-epfpoptlridodxeoimfrfaaRgtemmlyeen12ts0s%c.oAnotfacitnhhirenogpmRromatteeoo1mgisre8a.p2[1-hf1o]i,lcdaaonnfddailtmhyeestihpsyroolatfreghoimeniaincretss/,tkuaindddyney tissue hydrolysattehse sahbuonwdaendcethoaf tRRmme2ea2ias l2e-fvoeldl iosfhRimghe2esr. tAhachnroRmmateo2gsrabpyhic5–a6nafloysldis [o4f]h. eart/kidney tissue hydrolysates showed that Rme2a level is higher than Rme2s by 5–6 fold [4]
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