1、Lysine Methyltransferase SubstratesLysine MethylationDynamic RegulationLysine Methylation of Non-histone Proteins:An Expanding LandscapeDynamic p53 MethylationRas-MAPK SignalingMethyllysine ReadersKMTHistonesNon-histonesNSD3H3(K36)Kme0&1EGFR(K721)Kme0MBDHistonesNon-histonesBINDING SITEme1/2/3HP1MPP8
2、H3(K9me3)H3(K9me3)DNA-PKcs(K1150/2746/3248me2/3)DNMT3a(K44me2)GLP(K205me2)MBTK370me2Growth factor bindingK382me2K382meK373me2K372meK370meK260ororL3MBTL1 H1(K26me2)p53(K382me2)RB1(K860me)TudorChromo53BP1PHF20H4(K20me1/2)H3(K4me2)H4(K20me2)p53(K370/382me2)RB1(K810me1/2)p53(K370/382me2)ESR(K235me2)SETD
3、1AH3(K4)Kme0,1&2HSP70(K561)Kme1SETD1BH3(K4)Kme0,1&2TAT(K50/51)Kme2SETD7H3(K4)Kme0P53(K372)RB1(K810/873)E2F1(K185)RELA(K37/314/315)TAF7(K5)TAF10(K189)YAP(K494)STAT3(K140)FoxO3(K270/271)MYPT1(K442)IRF1/2(K126/134)PIAS2(K2076)ESR(K302)AR(K630/632)FXR(K206)GFI-1B(K8)CENPC(K414)MECP2(K347)PARP1(K508)PPAR
4、BP(K1006)DNMT1(K142/1094)Suv39H1(K105/123)PCAF(K78/89)SIRT1(K233/235/236/238)TTK(K708/710)CULLIN1(K73)TAT(K51)ZDHHC8(K300)AKAP6(K604)Kme0Kme0Kme0Kme0Kme0Kme0Kme0Kme1Kme0Kme0Kme0&1Kme1Kme0Kme0undefnedKme1Kme0Kme0Kme0undefnedKme0Kme0Kme0Kme0undefnedundefnedKme0Kme0undefnedSETD6 RELA(K310)Kme0METTL21B
5、EEF1A(K165)Kme2METTL21D VCP/p97(K315)Kme2METTL22 KIN17(K135)Kme2SETDB1EZH2H3(K9)H3(K27)Kme0,1&2Kme1&2P53(K370)STAT3(K180)GATA4(K299)ROR(K38)Kme1undefnedKme0Kme0GLPH3(K9)H1.2(K187)Kme0&1Kme0&1P53(K373)DNMT3a(K44)GLP(K205)Kme1Kme1Kme1SETD8H4(K20)Kme0P53(K382)PCNA(K248)Numb(K158/163)Kme0Kme0Kme0&1SMYD3
6、H4K5Kme0,1&2MAP3K2(K260)VEGFR(K831)Kme0,1&2Kme1SMYD2 P53(K370)RB1(K810/860)ESR(K266)HSP90(K209/615)MAPKAPK3(K355)Kme0Kme0undefnedKme0Kme0METTL10METTL21A EF1A(K318)HSP72(K561)HSP70-2(K563)GRP78(K585)HSP70B(K563)HSC70(K561)Kme2Kme2Kme2Kme2Kme2Kme2G9aH3(K9)H1.2(K187)Kme0&1Kme0&1P53(K373)MEF2D(K276)MTA1
7、(K532)RuvBL2(K67)C/EBP(K39)MyoD(K104)WIZ(K305)KLF12(K313)EED(K66/197/268/284)DNMT1(K70)DNMT3a(K44)G9a(K165/239)GLP(K174)GLP(K205)MAM(K16)CDYL1(K135)HDAC1(K432)ACINUS(K654)Reptin(K67)Kme1Kme0&1Kme1Kme0undefnedKme0&1Kme2Kme0Kme1Kme1Kme1Kme1&2Kme0Kme1undefnedKme2undefnedKme2undefnedCellular development
8、(502)Regulation of apoptosis(245)Cell cycle(326)Cell-cell adhesion(177)Protein translation(131)G protein-coupled receptor signaling(53)Regulation of p53 signal translation(48)Protein folding(76)Protein transport(170)Protein sumoylation(46)Transcription(486)Chromatin remodeling(60)Gene silencing(58)R
9、NA processing(292)DNA repair(143)RNA transport(61)NH3+NH2+N+Methyllysine reader proteinChromo,Tudor,MBT,etc.Methylated binding partnerNH+Kand/orand/orKKLysine(K)Kme1Kme2Kme3KMTKDMKMTKDMKMTKDMKMTKDMCH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3CH3LysineSUBSTRATELysineSUBSTRATERTKVEGFR1K831p53p53p53p53p53p53p53KMT
10、KDMLSD1KMTSET8 KDMG9a KDMSET7KDMSMYD2LSD1Inactive p53Growth and TumorigenesisActive p53PPMeRASRAFPMEKPERKPMAP3K2PMePP2ASMYD353BP153BP1PHF20PHF20L3MBTL1MeMeMeMeMeMe MeMeMeSnapShot:Lysine Methylation beyond HistonesKyle K.Biggar,1,2 Zhentian Wang,3 and Shawn S.-C.Li21Institute of Biochemistry,Carleton
11、 University,Ottawa,ON,Canada;2Department of Biochemistry,Western University,London,ON,Canada;3Department of Biology,Stanford University,Stanford,CA,USA1016 Molecular Cell 68,December 7,2017 2017 Published by Elsevier Inc.DOI http:/dx.doi.org/10.1016/j.molcel.2017.11.018See online version for legend
12、and references.1016.e1 Molecular Cell 68,December 7,2017 2017 Published by Elsevier Inc.DOI http:/dx.doi.org/10.1016/j.molcel.2017.11.018SnapShot:Lysine Methylation beyond HistonesKyle K.Biggar,1,2 Zhentian Wang,3 and Shawn S.-C.Li21Institute of Biochemistry,Carleton University,Ottawa,ON,Canada;2Dep
13、artment of Biochemistry,Western University,London,ON,Canada;3Department of Biology,Stanford University,Stanford,CA,USAWhile the majority of studies on lysine methylation to date were focused on histones in the context of the chromatin,non-histone proteins have emerged as common methyla-tion substrat
14、es in recent years.The methylation of proteins other than histones extends the role of lysine methylation beyond epigenetics.This SnapShot is intended to provide a birds eye view of the current state of non-histone lysine methylation and its involvement in a wide spectrum of biological processes ins
15、ide as well as outside the nucleus.The Writers,Erasers,and Readers of Lysine MethylationThe e-NH2 on lysine may be modified by one,two,or three methyl groups to form mono-,di-,or tri-methylated lysine(Kme1,Kme2,and Kme3),respectively.This process is catalyzed by lysine-specific methyltransferases(KM
16、Ts)and reversed by lysine demethylases(KDMs).The human genome encodes an estimated 52 KMTs and 32 KDMs,many of which are evolutionarily conserved.Lysine methylation may lead to changes in the activity or intracellular localization of the modified substrate or its interaction with regulatory or effec
17、tor proteins that contain a methylation-binding domain(MBD).Approximately 148 MBDs,including the chromo,tudor,and MBT domains,have been identified in humans,making it one of the largest families of post-translational modification(PTM)“readers.”Lysine Methylation of Non-histone ProteinsRecent advance
18、ment in mass spectrometry and innovative strategies for isolating methylated proteins or peptides have led to the identification of 5,000 methyllysine(Kme)sites.The current landscape of the Kme proteome has implicated lysine methylation in a wide range of cellular functions or processes(Biggar and L
19、i,2015).While it is not sur-prising to find nuclear proteins,including many mediating gene transcription and RNA processing,that are methylated,it is intriguing that hundreds of cytosolic or membrane proteins involved in development,cell-cell interaction,or signal transduction are methylated on lysi
20、ne.Lysine methylation functions both inside and outside the nucleus to regulate almost all essential cellular processes.Regulation of Cellular Functions by Lysine MethylationRecent studies have started to shed light on how lysine methylation affects protein activity or signal transduction to modulat
21、e cellular or pathological processes(Dhami et al.,2013).For example,p53,an important regulator of the cell cycle,apoptosis,and the DNA damage response,is found methylated on K370,K372,K373,and K382 in a highly coordinated fashion by a group of KMTs and KDMs(Shi et al.,2007;West and Gozani,2011).Intr
22、iguingly,the site and degree of methylation and the subsequent recruitment of different MBD-containing effector proteins dictate the outcome of methylation for p53(Cui et al.,2012).This serves as a prototypical example of how dynamic methylation may regulate substrate activity in exquisite,and somet
23、imes opposite,ways.Moreover,the interplay between Ser/Thr or Tyr phosphorylation and lysine methylation have been shown to regulate signaling fidelity,thresholds,and dynamics in a variety of different signaling pathways.As an example of how lysine methylation exerts regulatory control over a signal
24、transduction process,it was recently shown that the stress-induced MAPK kinase kinase 2(MAP3K2)is methylated at K260 by the KMT SMYD3(Mazur et al.,2014).This methylation event blocks the dephosphorylation of a neighboring phosphorylation site on MAP3K2 by the phosphatase PP2A,resulting in an increas
25、e in the activity for the downstream kinases MEK1/2 and ERK1/2.ABBREVIATIONSKme,methyllysine;KMT,lysine methyltransferase;KDM,lysine demethylase;MBD,methylation-binding domain;SAM,S-adenosyl methionine;PTM,post-translational modification.REFERENCESBiggar,K.K.,and Li,S.S.C.(2015).Nat.Rev.Mol.Cell Bio
26、l.16,517.Cui,G.,Park,S.,Badeaux,A.I.,Kim,D.,Lee,J.,Thompson,J.R.,Yan,F.,Kaneko,S.,Yuan,Z.,Botuyan,M.V.,et al.(2012).Nat.Struct.Mol.Biol.19,916924.Dhami,G.K.,Liu,H.,Galka,M.,Voss,C.,Wei,R.,Muranko,K.,Kaneko,T.,Cregan,S.P.,Li,L.,and Li,S.S.(2013).Mol.Cell 50,565576.Mazur,P.K.,Reynoird,N.,Khatri,P.,Jansen,P.W.,Wilkinson,A.W.,Liu,S.,Barbash,O.,Van Aller,G.S.,Huddleston,M.,Dhanak,D.,et al.(2014).Nature 510,283287.Shi,X.,Kachirskaia,I.,Yamaguchi,H.,West,L.E.,Wen,H.,Wang,E.W.,Dutta,S.,Appella,E.,and Gozani,O.(2007).Mol.Cell 27,636646.West,L.E.,and Gozani,O.(2011).Epigenomics 3,361369.
