Circadian Clock Proteins.pdf

See online version for legend and references368 Cell 135,October 17,2008 2008 Elsevier Inc.DOI 10.1016/j.cell.2008.09.042SnapShot:Circadian Clock ProteinsElizabeth E.Hamilton and Steve A.KayDivision of Biological Sciences,University of California San Diego,La Jolla,CA 92093,USAProteinclock FunctionPeak expressionPost-translational RegulationRnA Protein Mammalcore Loop(cL)cLOcK:bHLH-PAS transcription factor,HATDimerizes with BMAL1 to bind E box(CACGTG),activating transcription of per,cry,rev-erbConstantConstantRhythmic phosphorylationBMAL1:bHLH-PAS transcription factorDimerizes with CLOCK to bind E box(CACGTG),activating transcription;ortholog of fl y CYC152108PhosphorylationPeR1,2:PAS domainDimerizes with CRY to inhibit CLOCK-BMAL1 transcriptional activity46,6121014Progressive phosphorylationcRY1,2:Flavoprotein;repressor domainDimerizes with PER to inhibit CLOCK-BMAL18141218NoInterlocking Loops(IL)ROR,:Orphan nuclear receptorActivates Bmal1 transcription812ReV-eRB,:Orphan nuclear receptorRepresses Bmal1 transcription26Dec1,2:bHLH-ORANGE transcription factorRepresses transcription from E box(CACGTG)driven promoters;ortholog of fl y CWO2,62,6DBP:bZIP-PAR transcription factorActivates per transcription466e4BP4:bZIP transcription factorRepresses per transcription;ortholog of fl y VRI161620DrosophilacLcLK:bHLH-PAS transcription factorDimerizes with CYC to bind E box(CACGTG),activates per,tim,vri,Pdp1 transcription0ConstantRhythmic phosphorylationcYc:bHLH-PAS transcription factor;HATDimerizes with CLK to bind E box(CACGTG),activates per,tim,vri,Pdp1 transcription;ortholog of mammal BMAL1ConstantConstantNoPeR:PAS domainDimerizes with TIM to inhibit CLK-CYC transcription activity151721Progressive phosphorylationTIM:Putative Armadillo and HEAT domainsDimerizes with PER1220Progressive phosphorylationILPDP1:bZIP transcription factorActivates Clk transcription1821NoVRI:bZIP transcription factorRepresses Clk transcription;ortholog of mammal E4BP41414PhosphorylationcWO:bHLH-ORANGE transcription factorBinds to E box(CACGTG)to repress CLK-mediated transcription;ortholog of mammal DEC1/21215NeurosporacLWc-1:PAS/LOV transcription factor;HATDimerizes with WC-2 to activate frq transcription;blue-light photoreceptorConstant1820PhosphorylationWc-2:PAS transcription factorDimerizes with WC-1 to activate frq transcriptionConstantConstantNoFRQ:Coiled-coil,PEST domainHomodimerizes to regulate WC-1/WC-2 dimer activity and abundance068Progressive phosphorylationILVVD:PAS/LOV domainNegative regulator of light responses to core loop;blue-light photoreceptor012ArabidopsiscLTOc1:Pseudo-receiver and CCT domainsActivates transcription of LHY and CCA1101212Progressive phosphorylationLUX:MYB transcription factorActivates transcription of LHY and CCA11212eLF4:UnknownActivates transcription of LHY and CCA112ccA1/LHY:MYB transcription factorBinds to evening element(AAAATATCT)inhibiting transcription of TOC1,LUX,ELF4,GI,ELF3;activates PRR5,7,9 transcription013PhosphorylationILGI:UnknownStabilizes ZTL promoting TOC1 degradation8101113PRR3:Pseudo-receiver and CCT domainsStabilizes TOC1 inhibiting ZTL binding to TOC11013Progressive phosphorylationPRR5:Pseudo-receiver and CCT domainsInhibits CCA1/LHY transcription8911PhosphorylationPRR7:Pseudo-receiver and CCT domainsInhibits CCA1/LHY transcription6810Progressive phosphorylationPRR9:Pseudo-receiver and CCT domainsInhibits CCA1/LHY transcription24810eLF3:UnknownNegative regulator of light responses to CL1616Proteinclock FunctionRegulatorsMammalcK1:KinaseRegulates PERcK1:KinaseRegulates PER,CRY,BMAL1GsK3:KinaseRegulates PER,CRY,REV-ERBPP1:PhosphataseRegulates PERPP2A:PhosphataseRegulates PERPP5:PhosphataseRegulates CK1TrcP:F box proteinTargets PER for degradationFBXL3:F box proteinTargets CRY for degradationDrosophilaDBT:KinaseRegulates PER and CLKcK2:KinaseRegulates PERsGG:KinaseRegulates TIMPP2A:PhosphataseRegulates PER and CLKsLMB:F box proteinTargets PER for degradationJeT:F box proteinTargets TIM for degradationNeurosporacK1:KinaseRegulates FRQcK2:KinaseRegulates FRQPP1:PhosphataseRegulates FRQPP2A:PhosphataseRegulates FRQ and WC-1/WC-2 dimerFWD1:F box proteinTargets FRQ for degradationArabidopsiscK2:KinasePhosphorylates CCA1,LHYZTL:F box protein and PAS/LOV domainTargets TOC1 and PRR5 for degradationSnapShot:Circadian Clock ProteinsElizabeth E.Hamilton and Steve A.KayDivision of Biological Sciences,University of California San Diego,La Jolla,CA 92093,USA368.e1 Cell 135,October 17,2008 2008 Elsevier Inc.DOI 10.1016/j.cell.2008.09.042TableThe earths rotation about its axis generates predictable changes in light and temperature,which define the 24 hr day-night cycle.Organisms from bacteria to humans have evolved an internal timekeeper to anticipate these environmental changes.This timekeeperthe circadian clockallows organisms to parse biological processes to the appropriate time of day or night.Circadian clocks regulate behavioral,physiological,and metabolic rhythms via transcriptional feedback loops.Although clocks in different species use distinct protein constituents,the general architecture is conserved:A network of interconnected transcriptional feedback loops regulates rhythmic transcription of loop components as well as clock output genes.These interconnected loops consist of a core loop(CL)with a number of interlocking loops(IL)intersecting it.The primary difference between these loops is the effect of mutations on clock behavior.Mutating components of the core loop severely affects the regulation of the clock,whereas the effects are much milder for components in the interlocking loops.Posttranslational regulation such as phosphorylation introduces small delays ensuring that feedback regulators function at the correct time and cellular location to maintain 24 hr rhythms in transcription.The complexity of these transcriptional feedback loops for simply maintaining 24 hr timekeeping may not be a universal requirement.Recent work in cyanobacteria,a prokaryote,shows that a 24 hr oscillator can be reconstituted in vitro by three purified proteins(see Nakajima et al.,2005).Peak phases for RNA and protein expression outlined in the table are in Zeitgeber time(ZT),where dawn(lights on)is ZT0 and dusk(lights off)is ZT12.A dash(“”)indicates data that have not been reported.Mammalian phase data were determined for the suprachiasmatic nucleus(SCN).FigureAt the heart of the eukaryotic clock are interlocking,autoregulatory feedback loops.In the core loop of the mammalian clock,positive elements CLOCK and BMAL1(circles)heterodimerize and initiate transcription of their negative regulators PER and CRY(rounded squares).As the concentration of PER and CRY accumulates,these proteins form multimers,are phosphorylated,and translocate to the nucleus where they repress their own transcription by interacting with CLOCK-BMAL1 heterodimers.Phosphorylation-induced degradation of PER and CRY decreases their concentrations,which reactivates the positive elements,allowing the cycle to start again.Core loop components also activate multiple ccgs(clock-controlled genes)to form interlocking positive-and negative-feedback loops that are important for maintaining robustness of the clock.In mam-mals,CLOCK-BMAL1 heterodimers activate transcription of ROR and REV-ERB(green square),which provide additional positive and negative feedback,respectively,to transcription of BMAL1.AbbreviationsTrCP,-transduction repeat-containing protein;bHLH,basic helix-loop-helix;BMAL1,brain and muscle ARNT-like protein 1;bZIP,basic leucine zipper motif;CCA1,cir-cadian clock associated 1;ccgs,clock-controlled genes;CCT,constans,constans-like,TOC1;CK,casein kinase;CLK/CLOCK,circadian locomotor output cycle kaput(CLOCK);CRY,cryptochrome;CWO,clockwork orange;CYC,cycle;DBP,D binding protein;DBT,doubletime;DEC,differentially expressed in chondrocytes;E4BP4,E4 promoter-binding protein;ELF,early flowering;FBXL3,F box and leucine-rich repeat protein 3;FRQ,frequency;FWD-1,F box and WD40-repeat-contiaining protein-1;GI,gigantea;GSK3,glycogen synthase kinase-3;HAT,histone acetyltransferase;HEAT,Huntington elongation factor 3,A subunit of protein phosphotase 2A and TOR1;JET,jetlag;LHY,late elongated hypocotyl;LOV,light,oxygen,voltage domain;LUX,lux arrhythmo;PAR,proline and acidic amino acid-rich;PAS,period-ARNT-single-minded;PDP1,PAR domain protein1;PER,period;PEST,proline,glutamic acid,serine,and threonine;PP,protein phosphotase;PRR,pseudo-response regulator;ROR,retinoic acid-related orphan receptor;SGG,shaggy;SLMB,supernumerary limbs(SLIMB);TIM,timeless;TOC1,timing of CAB expression 1;VRI,vrille;VVD,vivid;WC,white collar;ZTL,zeitlupeReFeRencesBell-Pedersen,D.,Cassone,V.M.,Earnest,D.J.,Golden,S.S.,Hardin,P.E.,Thomas,T.L.,and Zoran,M.J.(2005).Circadian rhythms from multiple oscillators:Lessons from diverse organisms.Nat.Rev.Genet.6,544556.Brunner,M.,and Kldi,K.(2008).Interlocked feedback loops of the circadian clock of 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