OpinionMechanismsforActiveRegulationofBiomolecularCondensatesJohannesSo¨ding,1,*DavidZwicker,2SalmaSohrabi-Jahromi,1MarcBoehning,3andJanKirschbaum2Liquid–liquidphaseseparationisakeyorganizationalprincipleineukaryoticcells,onparwithintracellularmembranes.Itallowscellstoconcentratespecificproteinsintocondensates,increasingreactionratesandachievingswitch-likeregulation.Weproposetwoactivemecha-nismsthatcanexplainhowcellsregulatecondensateformationandsize.Inboth,thecellregu-latestheactivityofanenzyme,oftenakinase,thataddspost-translationalmodificationstocondensateproteins.Inenrichmentinhibition,theenzymeenrichesinthecondensateandweakensinteractions,asseeninstressgranules(SGs),Cajalbodies,andPgranules.Inlocaliza-tion-induction,condensatesformaroundimmobilizedenzymesthatstrengtheninteractions,asobservedinDNArepair,transmembranesignaling,andmicrotubuleassembly.Thesemodelscanguidestudiesintothemanyemergingrolesofbiomolecularcondensates.BiomolecularCondensatesCanBeFormedandDissolvedintheBlinkofanEnzymeEukaryoticcellspossessnumeroustypesofmembranelessorganelles(seeGlossary).EachcontainsbetweentensandseveralthousandsofproteinandRNAspeciesthatarehighlyenrichedcomparedwiththesurroundingnucleoplasmorcytoplasm.Thesebiomolecularcondensatesareheldtogetherbyweak,multivalent,andhighlycollaborativeinteractions,oftenbetweenintrinsicallydisorderedre-gionsoftheirconstituentproteins[1,2].Incontrasttomembrane-boundorganelles,biomolecularcondensatescaneasilybeformedordis-solvedbymerelychangingtheactivityofanenzyme,suchasakinase,thatpost-translationallymod-ifieskeycondensateproteins[3–5,71].Themodificationsusuallylieinintrinsicallydisorderedregionsandmodulatethestrengthofattractiveinteractionswithothercondensatecomponents[6,7].Duetothehighlycooperativenatureofphasetransitions,smallchangesininteractionstrengthscanresultintheformationordissolutionofcondensates,andthisswitch-likenaturemakesthemidealfordynamicregulation.Forinstance,SGsformoncellularstressandaredissolvedwhenthestressceases[3]...
