Characterization of SETD3 methyltransferase–mediated protein methionine methylation

Abstract

Most characterized protein methylation events encompass arginine and lysine N-methylation, and only a few cases of protein methionine thiomethylation have been reported. Newly discovered oncohistone mutations include lysine-to-methionine substitutions at positions 27 and 36 of histone H3.3. In these instances, the methionine substitution localizes to the active-site pocket of the corresponding histone lysine methyltransferase, thereby inhibiting the respective transmethylation activity. SET domain–containing 3 (SETD3) is a protein (i.e. actin) histidine methyltransferase. Here, we generated an actin variant in which the histidine target of SETD3 was substituted with methionine. As for previously characterized histone SET domain proteins, the methionine substitution substantially (76-fold) increased binding affinity for SETD3 and inhibited SETD3 activity on histidine. Unexpectedly, SETD3 was active on the substituted methionine, generating S-methylmethionine in the context of actin peptide. The ternary structure of SETD3 in complex with the methionine-containing actin peptide at 1.9 Å resolution revealed that the hydrophobic thioether side chain is packed by the aromatic rings of Tyr312 and Trp273, as well as the hydrocarbon side chain of Ile310. Our results suggest that placing methionine properly in the active site—within close proximity to and in line with the incoming methyl group of SAM—would allow some SET domain proteins to selectively methylate methionine in proteins. Most characterized protein methylation events encompass arginine and lysine N-methylation, and only a few cases of protein methionine thiomethylation have been reported. Newly discovered oncohistone mutations include lysine-to-methionine substitutions at positions 27 and 36 of histone H3.3. In these instances, the methionine substitution localizes to the active-site pocket of the corresponding histone lysine methyltransferase, thereby inhibiting the respective transmethylation activity. SET domain–containing 3 (SETD3) is a protein (i.e. actin) histidine methyltransferase. Here, we generated an actin variant in which the histidine target of SETD3 was substituted with methionine. As for previously characterized histone SET domain proteins, the methionine substitution substantially (76-fold) increased binding affinity for SETD3 and inhibited SETD3 activity on histidine. Unexpectedly, SETD3 was active on the substituted methionine, generating S-methylmethionine in the context of actin peptide. The ternary structure of SETD3 in complex with the methionine-containing actin peptide at 1.9 Å resolution revealed that the hydrophobic thioether side chain is packed by the aromatic rings of Tyr312 and Trp273, as well as the hydrocarbon side chain of Ile310. Our results suggest that placing methionine properly in the active site—within close proximity to and in line with the incoming methyl group of SAM—would allow some SET domain proteins to selectively methylate methionine in proteins. Post-translational methylation on proteins, particularly histones, plays a fundamental role in regulating gene expression and chromatin organization (1Paik W.K. Paik D.C. Kim S. Historical review: the field of protein methylation.Trends Biochem. Sci. 2007; 32 (17291768): 146-15210.1016/j.tibs.2007.01.006Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 2Shechter D. Introduction to the multi-author review on methylation in cellular physiology.Cell. Mol. Life Sci. 2019; 76 (31177294): 2871-287210.1007/s00018-019-03141-1Crossref PubMed Scopus (5) Google Scholar, 3Tolsma T.O. Hansen J.C. Post-translational modifications and chromatin dynamics.Essays Biochem. 2019; 63 (31015385): 89-9610.1042/EBC20180067Crossref PubMed Scopus (39) Google Scholar). For example, histone H3 methylation at lysine residues 4, 9, 27, 36, and 79 signals for gene activation or repression of transcription. Dysregulation of these epigenetic signals has been correlated with and mechanistically linked to many human disorders including cancer (4Zhao Z. Shilatifard A. Epigenetic modifications of histones in cancer.Genome Biol. 2019; 20 (31747960): 24510.1186/s13059-019-1870-5Crossref PubMed Scopus (192) Google Scholar, 5Allis C.D. Jenuwein T. The molecular hallmarks of epigenetic control.Nat. Rev. Genet. 2016; 17 (27346641): 487-50010.1038/nrg.2016.59Crossref PubMed Scopus (1328) Google Scholar, 6Butler J.S. Koutelou E. Schibler A.C. Dent S.Y. 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Gilbertson R.J. et al.Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas.Nat. Genet. 2012; 44 (22286216): 251-25310.1038/ng.1102Crossref PubMed Scopus (1094) Google Scholar) (reviewed in Ref. 9Lowe B.R. Maxham L.A. Hamey J.J. Wilkins M.R. Partridge J.F. Histone H3 mutations: an updated view of their role in chromatin deregulation and cancer.Cancers (Basel). 2019; 11 (31086012): 66010.3390/cancers11050660Crossref PubMed Scopus (62) Google Scholar and the references therein). The most heavily characterized oncohistone mutations are the lysine-to-methionine mutants at K27M and K36M, which perturb the methylation site for specific lysine methyltransferases (MTases) and dominantly inhibit methylation of corresponding lysine residues in other histone H3 proteins. Structural characterization of histone MTases in complex with the methionine-substituted histone H3 peptides, including G9a-H3K9M (10Shan C.M. Wang J. Xu K. Chen H. Yue J.X. Andrews S. Moresco J.J. Yates J.R. Nagy P.L. Tong L. Jia S. A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading.eLife. 2016; 5 (27648579): e1790310.7554/eLife.17903Crossref PubMed Scopus (26) Google Scholar, 11Jayaram H. Hoelper D. Jain S.U. Cantone N. Lundgren S.M. Poy F. Allis C.D. Cummings R. Bellon S. Lewis P.W. S-Adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3.Proc. Natl. Acad. Sci. U.S.A. 2016; 113 (27185940): 6182-618710.1073/pnas.1605523113Crossref PubMed Scopus (58) Google Scholar), PRC2-H3K27M (12Justin N. Zhang Y. Tarricone C. Martin S.R. Chen S. Underwood E. De Marco V. Haire L.F. Walker P.A. Reinberg D. Wilson J.R. Gamblin S.J. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2.Nat. Commun. 2016; 7 (27121947): 1131610.1038/ncomms11316Crossref PubMed Scopus (244) Google Scholar), and SETD2-H3K36M (13Yang S. Zheng X. Lu C. Li G.M. Allis C.D. Li H. Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase.Genes Dev. 2016; 30 (27474439): 1611-161610.1101/gad.284323.116Crossref PubMed Scopus (82) Google Scholar), revealed that the methionine residue localizes to the active-site pocket that normally accommodates the target lysine residue, thereby inhibiting the respective transmethylation activity. In vitro, it was the study of LSD1 (a histone H3K4me2/1 demethylase) that first used a H3 peptide bearing methionine in place of methyl-Lys4 (PDB code 2V1D), which showed that the K4M peptide is a strong inhibitor of LSD1 because the methionine substitution led to a 30-fold increase in binding affinity (14Forneris F. Binda C. Adamo A. Battaglioli E. Mattevi A. Structural basis of LSD1-CoREST selectivity in histone H3 recognition.J. Biol. Chem. 2007; 282 (17537733): 20070-2007410.1074/jbc.C700100200Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Interestingly, EZHIP (enhancer of zeste homologs inhibitory protein) inhibits PRC2 methylation activity by presenting a methionine-containing, naturally occurring, H3K27M-like sequence (15Hübner J.M. Müller T. Papageorgiou D.N. Mauermann M. Krijgsveld J. Russell R.B. Ellison D.W. Pfister S.M. Pajtler K.W. Kool M. EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.Neuro. Oncol. 2019; 21 (30923826): 878-88910.1093/neuonc/noz058Crossref PubMed Scopus (78) Google Scholar, 16Jain S.U. Do T.J. Lund P.J. Rashoff A.Q. Diehl K.L. Cieslik M. Bajic A. Juretic N. Deshmukh S. Venneti S. Muir T.W. Garcia B.A. Jabado N. Lewis P.W. PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like Commun. 2019; PubMed Scopus Google Scholar, A. M. N. D.C. Shilatifard A. gene that methylation activity of repressive complex an H3K27M-like 2019; 5 PubMed Scopus (62) Google Scholar, R. R. S. K. D. A. M. M. S. N. D. et polycomb repressive complex activity in Commun. 2019; PubMed Scopus Google Scholar), a role for these in the methyl is the of methionine The of the active methyl and Chem. Scopus Google Scholar), which a group M.A. D. a of Mol. Life Sci. 63 PubMed Scopus Google Scholar, M. T.A. is an Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the to S-methylmethionine by a by methionine J.M. of methionine and lysine in Scopus Google Scholar). the of methionine methylation is characterized in the context of the of protein methionine methylation is of protein methionine methylation are to in a activity active on in the M. Paik W.K. and characterization of that methylate methionine and arginine residues of Biol. Chem. Full Text PDF PubMed Google Scholar) and an of in the J.M. A in the protein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). SETD3 was as the first histidine that on an actin histidine residue S. D. M. T. M. M. J. SETD3 protein is the histidine 7 PubMed Scopus Google Scholar, J. S. Liu S. D. Li J.R. Zhang X. Liu C. J. et is an actin histidine methyltransferase that 2019; PubMed Scopus Google Scholar, J. E. J.R. J. Ding S. G. Xu J. T. E. et the methyltransferase 2019; 4 PubMed Scopus Google Scholar, S. S. H. G. X. J. J. Xu C. Structural histidine methylation on 2019; PubMed Scopus Google Scholar). have that SETD3 a of with characterized protein lysine MTases and and that SETD3 has lysine methylation activity on an actin variant in which the target is substituted by a lysine S. J.R. Zhang X. X. Structural basis for the target of actin histidine methyltransferase Commun. 2019; PubMed Scopus Google Scholar, S. J.R. Zhang X. X. variant of SETD3 methyltransferase target histidine to lysine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). by the inhibitory of oncohistone mutations of lysine-to-methionine and MTases inhibiting we that SETD3 has methylation activity on an actin variant in which the target is substituted by a methionine the and molecular of generating S-methylmethionine in the context of a protein peptide. Our of SETD3 that SETD3 in activity on activity S. J.R. Zhang X. X. Structural basis for the target of actin histidine methyltransferase Commun. 2019; PubMed Scopus Google Scholar) we SETD3 activity on in which the target was substituted by a methionine As a activity was on in which was by an with the SETD3 on peptide bearing or methionine at the of in which SETD3 on we activity on and activity on As the methyl a group and MTases the target in a In with SETD3 has an of 7 and for histidine the a is and a of for lysine because of of S. J.R. Zhang X. X. Structural basis for the target of actin histidine methyltransferase Commun. 2019; PubMed Scopus Google Scholar). In methionine has a thioether side and SETD3 has a activity on a of with a increase of activity at at the of SETD3 has a of on methylation S. J.R. Zhang X. X. variant of SETD3 methyltransferase target histidine to lysine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), SETD3 is a on (i.e. the the is the we that SETD3 showed an activity on with an of we the SETD3 and peptide by a of an increase of binding by a of 76 the SETD3 of which the of of binding by the methionine-substituted peptide with on LSD1 (14Forneris F. Binda C. Adamo A. Battaglioli E. Mattevi A. Structural basis of LSD1-CoREST selectivity in histone H3 recognition.J. Biol. Chem. 2007; 282 (17537733): 20070-2007410.1074/jbc.C700100200Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar) and PRC2 (12Justin N. Zhang Y. Tarricone C. Martin S.R. Chen S. Underwood E. De Marco V. Haire L.F. Walker P.A. Reinberg D. Wilson J.R. Gamblin S.J. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2.Nat. Commun. 2016; 7 (27121947): 1131610.1038/ncomms11316Crossref PubMed Scopus (244) Google Scholar). In the well with the of 32 G9a and H3 peptide with the with in the of H. Hoelper D. Jain S.U. Cantone N. Lundgren S.M. Poy F. Allis C.D. Cummings R. Bellon S. Lewis P.W. S-Adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3.Proc. Natl. Acad. Sci. U.S.A. 2016; 113 (27185940): 6182-618710.1073/pnas.1605523113Crossref PubMed Scopus (58) Google Scholar). the that activity of SETD3 on is the peptide inhibits SETD3 activity on with an of with G9a inhibition by H3 peptide with of H. Hoelper D. Jain S.U. Cantone N. Lundgren S.M. Poy F. Allis C.D. Cummings R. Bellon S. Lewis P.W. S-Adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3.Proc. Natl. Acad. Sci. U.S.A. 2016; 113 (27185940): 6182-618710.1073/pnas.1605523113Crossref PubMed Scopus (58) Google Scholar). SETD3 was with the peptide in the of and we for peptide residues The ternary structure was to resolution of 1.9 Å The structure is to the previously of SETD3 in complex with (PDB code (PDB code or (PDB code with of Å of of structure in the in group In the active site the of is Å the of in which a methyl group The of the side chain and the methionine of in the active site is to other by a of The thioether side chain is packed in the aromatic rings of Tyr312 the and The of is in with the chain of the of and the side chain of In the chain of of actin a of S. in structure and Biol. Chem. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar) with side chain of The to binding of in an active site of aromatic and hydrophobic a to the as by the of for a lysine the hydrophobic in a S. Structural and of a residue the hydrophobic of 30 PubMed Scopus Google Scholar). the mutations of the residue for with S. J.R. Zhang X. X. Structural basis for the target of actin histidine methyltransferase Commun. 2019; PubMed Scopus Google Scholar) to hydrophobic residues and activity for methylation by and we the structure of in complex with the peptide to resolution of Å The structure is to that of the with a of Å of The increased of with the of associated with the side chain of of actin to to the methyl the of the complex with that of histone H3 MTases and in complex with methionine mutations at lysine 9, 27, and 36, (10Shan C.M. Wang J. Xu K. Chen H. Yue J.X. Andrews S. Moresco J.J. Yates J.R. Nagy P.L. Tong L. Jia S. A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading.eLife. 2016; 5 (27648579): e1790310.7554/eLife.17903Crossref PubMed Scopus (26) Google Scholar, N. Zhang Y. Tarricone C. Martin S.R. Chen S. Underwood E. De Marco V. Haire L.F. Walker P.A. Reinberg D. Wilson J.R. Gamblin S.J. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2.Nat. Commun. 2016; 7 (27121947): 1131610.1038/ncomms11316Crossref PubMed Scopus (244) Google Scholar, S. Zheng X. Lu C. Li G.M. Allis C.D. Li H. 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PubMed Scopus Google Scholar), on histone methionine substitution at lysine 4 or is active on respective peptide the with the corresponding methionine The activity with on peptide is to the of because was previously on lysine residues by X. A. Li R. S.Y. J. L. E. J. J. and of the of J. PubMed Scopus Google Scholar) The of activity on methionine by SETD3 as with other SET domain proteins on histone H3 the of their the histidine residue to the active site of SETD3 and positions the target and a the incoming methyl the of the lysine residue in an side chain in the target with the of peptide The on methionine by histone MTases the that the methionine side chain is in close proximity to the methyl group of for that in the of SETD3 with the side chain of is in a S. J.R. Zhang X. X. Structural basis for the target of actin histidine methyltransferase Commun. 2019; PubMed Scopus Google Scholar, S. J.R. Zhang X. X. variant of SETD3 methyltransferase target histidine to lysine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). G9a H. Hoelper D. Jain S.U. Cantone N. Lundgren S.M. Poy F. Allis C.D. Cummings R. Bellon S. Lewis P.W. S-Adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3.Proc. Natl. Acad. Sci. U.S.A. 2016; 113 (27185940): 6182-618710.1073/pnas.1605523113Crossref PubMed Scopus (58) Google Scholar), we and histone H3K9M in the of or which with G9a M. J. M. N. T. H. T. T. T. Y. Histone methyltransferases G9a and and are for methylation of at Dev. PubMed Scopus Google Scholar). the affinity for is that of and the methylation of actin peptide on by SETD3 in For the the only is the of the peptide and A with a with methylation was actin was with SETD3 The of the peptide was and by of of the peptide in an of a to The first is that is and results in a of The is that the of a to the results in an of and the of a that results the of an the is to the normally for by a which the in a of the of the these of in the of S-methylmethionine The methyl peptide 3 the on a is with a in with the of a of which and in the a to the in is with the S-methylmethionine and the of a and In we and in the that by the peptide the are in an of because of the and the of Here, we to of is to the of the are multiple of for the as S-methylmethionine on sequence and in The for of and in is in the of which is a a the that S-methylmethionine and with a because of the of the of the we that include or is the structure the of the peptide. it is that it with the associated with G. L.A. and a for peptide PubMed Scopus Google Scholar). A of protein methylation on of the protein and the side of and histidine and the of the side of and as well as the protein S. Biol. 5 PubMed Scopus Google Scholar). In to M. Paik W.K. and characterization of that methylate methionine and arginine residues of Biol. Chem. Full Text PDF PubMed Google Scholar, J.M. A in the protein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), we that the of methionine, in the context of an actin by the SETD3 in that of protein methionine methylation are generated by an methyltransferase in E. M. Paik W.K. and characterization of that methylate methionine and arginine residues of Biol. Chem. Full Text PDF PubMed Google Scholar) or of A. a of the J.M. A in the protein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that is the MTases X. to a of Biochem. Sci. Full Text Full Text PDF PubMed Scopus Google Scholar). and of methylation on methionine of a that is used in it is that have methylation to methionine with methionine methylation a of modifications and previously by including methionine methylation as a prevent The to the of the and are for a for methionine In to protein has been in a in a human methylation of which is by a protein and results in of binding L. Ding X. J. Xu H. Chen J. L. Y. J. Lu Liu L. Chen S. F. methylation in PubMed Scopus Google Scholar). The protein by the methyl group or to of residues C. J.C. V. H. G. A and activation by E. 20 Full Text Full Text PDF PubMed Scopus Google Scholar). and are the the hydrophobic and the these of the S-methylmethionine a and results in of function C. J.C. V. H. G. A and activation by E. 20 Full Text Full Text PDF PubMed Scopus Google Scholar, L. C. A. A. of PubMed Scopus Google Scholar, T. 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The of methionine is in active and methionine of the target to an increase in binding affinity for as well as for the with methionine substitution of target lysine of histone and inhibiting the on their that of methionine properly in the active to and in line with the incoming methyl group SETD3 and to methylate methionine. In many of the SET domain–containing proteins S.M. lysine methylation in the of cancer 2016; PubMed Scopus Google Scholar) have been and study that some of selectively methylate methionine in a protein human SETD3 and and in E. as as S. J.R. Zhang X. X. Structural basis for the target of actin histidine methyltransferase Commun. 2019; PubMed Scopus Google Scholar, S. J.R. Zhang X. X. variant of SETD3 methyltransferase target histidine to lysine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a was used to of and was used to the residues The SETD3 proteins at at in of 20 and The actin and at residue or by A ternary complex of peptide and was by the in a of and on for For the ternary complex of SETD3 and the at a of and on at by an the ternary or the well of and and the was used to The of the at was used to with Z. D. of A. PubMed Scopus Google Scholar). The previously structure of human SETD3 (PDB code was used as the in the molecular of R.J. 2007; PubMed Scopus Google Scholar, R.J. Biol. PubMed Scopus (1094) Google Scholar). used for the of the the of structure with J.J. N. Chen D.C. J.S. of in to at Biol. 2012; PubMed Scopus Google Scholar). and of K. for molecular Biol. PubMed Scopus Google Scholar, K. and of Biol. PubMed Scopus Google Scholar). The was used to the of the The molecular was used to on actin as previously S. J.R. Zhang X. X. Structural basis for the target of actin histidine methyltransferase Commun. 2019; PubMed Scopus Google Scholar). and with of in 20 5 and The at 30 by and by and For peptide the K. H. a and for of 2016; PubMed Scopus Google Scholar) was used to the methylation which is in a and is through a A with well an of 5 of was used to by a 4 A and with 20 or 20 The 20 is a of and The was at for by the of to a of and with 20 and The and 20 peptide and in the The was at and was at the with the of to The of 20 SETD3 and of peptide in the The at for The was the of the with The of methyltransferase and and respective peptide in the and at peptide histone H3 and used in the In by of 5 of the on an The was in for 30 and to at for A and with of peptide in the for 30 The of 20 peptide the for 20 at A was at SETD3 in 20 and was in the The actin in the the by a with the as The of was with a of 4 and the the was to by the a site by the by the in the binding to histone H3 peptide in the of or and with and in a of was on a A was to of and of was a with a and was by a A of and an of for the was by the in with the in for the actin and the actin are used in other most and for and and or and are by and with for was and The and structure have been to the and The have been to the the Jia for of used for activity of the for and for of with methyltransferase

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