A Proteomic Analysis of Arginine-methylated Protein Complexes

Arginine methylation is a post-translational modification that results in the formation of asymmetrical and symmetrical dimethylated arginines (a- and sDMA). This modification is catalyzed by type I and II protein-arginine methyltransferases (PRMT), respectively. The two major enzymes PRMT1 (type I) and PRMT5 (type II) preferentially methylate arginines located in RG-rich clusters. Arginine methylation is a common modification, but the reagents for detecting this modification have been lacking. Thus, fewer than 20 proteins have been identified in the last 40 years as containing dimethylated arginines. We have generated previously four arginine methyl-specific antibodies; ASYM24 and ASYM25 are specific for aDMA, whereas SYM10 and SYM11 recognize sDMA. All of these antibodies were generated by using peptides with aDMA or sDMA in the context of different RG-rich sequences. HeLa cell extracts were used to purify the protein complexes recognized by each of the four antibodies, and the proteins were identified by microcapillary reverse-phase liquid chromatography coupled on line with electrospray ionization tandem mass spectrometry. The analysis of two tandem mass spectra for each methyl-specific antibody resulted in the identification of over 200 new proteins that are putatively arginine-methylated. The major protein complexes that were purified include components required for pre-mRNA splicing, polyadenylation, transcription, signal transduction, and cytoskeleton and DNA repair. These findings provide a basis for the identification of the role of arginine methylation in many cellular processes. Arginine methylation is a post-translational modification that results in the formation of asymmetrical and symmetrical dimethylated arginines (a- and sDMA). This modification is catalyzed by type I and II protein-arginine methyltransferases (PRMT), respectively. The two major enzymes PRMT1 (type I) and PRMT5 (type II) preferentially methylate arginines located in RG-rich clusters. Arginine methylation is a common modification, but the reagents for detecting this modification have been lacking. Thus, fewer than 20 proteins have been identified in the last 40 years as containing dimethylated arginines. We have generated previously four arginine methyl-specific antibodies; ASYM24 and ASYM25 are specific for aDMA, whereas SYM10 and SYM11 recognize sDMA. All of these antibodies were generated by using peptides with aDMA or sDMA in the context of different RG-rich sequences. HeLa cell extracts were used to purify the protein complexes recognized by each of the four antibodies, and the proteins were identified by microcapillary reverse-phase liquid chromatography coupled on line with electrospray ionization tandem mass spectrometry. The analysis of two tandem mass spectra for each methyl-specific antibody resulted in the identification of over 200 new proteins that are putatively arginine-methylated. The major protein complexes that were purified include components required for pre-mRNA splicing, polyadenylation, transcription, signal transduction, and cytoskeleton and DNA repair. These findings provide a basis for the identification of the role of arginine methylation in many cellular processes. Protein arginine methylation is a post-translational modification that adds monomethyl or dimethyl groups to the guanidino nitrogen atoms of arginine (1Gary J.D. Clarke S. RNA and protein interactions modulated by protein arginine methylation.Prog. Nucleic Acid Res. Mol. Biol. 1998; 61: 65-131Google Scholar). The enzymes responsible for protein arginine methylation have been classified in two major classes; type I enzymes promote the formation of asymmetrical ω-NG,NG-dimethylated arginines (aDMA), 1The abbreviations used are: aDMA, asymmetrical ω-NG,NG-dimethylated arginine(s); sDMA, ω-NG,N′G-dimethylated arginine(s); DMA, dimethylated arginine; PRMT, protein-arginine methyltransferase; MBP, myelin basic protein; hnRNP, heterogeneous nuclear ribonucleoprotein; snRNP, small nuclear ribonucleoprotein; SMN, survival motor neuron; EWS, Ewing sarcoma protein; ATM, ataxia telangiectasia mutated protein; CPSF, cleavage and polyadenylation specificity factor; TLS, translocated liposarcoma protein; LC/MS/MS, liquid chromatography-tandem mass spectrometry; MALDI-TOF, matrix-assisted laser desorption ionization time-of-flight. and type II enzymes catalyze the formation of symmetrical ω-NG,N′G-dimethylated arginines (sDMA) (1Gary J.D. Clarke S. RNA and protein interactions modulated by protein arginine methylation.Prog. Nucleic Acid Res. Mol. Biol. 1998; 61: 65-131Google Scholar). ω-NG-Monomethylarginine is thought to be an intermediate formed by both enzyme types. The metabolic cost of methylation is high, requiring the use of 12 ATP molecules/methylation event (1Gary J.D. Clarke S. RNA and protein interactions modulated by protein arginine methylation.Prog. Nucleic Acid Res. Mol. Biol. 1998; 61: 65-131Google Scholar). The fact that evolution has retained such an “expensive” reaction underscores the biological importance of this post-translational modification (2McBride A. Silver P. State of the Arg: protein methylation at arginines comes of age.Cell. 2001; 106: 5-8Google Scholar). There are now at least five type I protein-arginine methyltransferases in mammals; PRMT1 (3Lin W.J. Gary J.D. Yang M.C. Clarke S. Herschman H.R. The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase.J. Biol. Chem. 1996; 271: 15034-15044Google Scholar), PRMT2 (4Scott H.S. Antonarakis S.E. Lalioti M.D. Rossier C. Silver P.A. Henry M.F. Identification and characterization of two putative human arginine methyltransferases (HRMT1L1 and HRMT1L2).Genomics. 1998; 48: 330-340Google Scholar), PRMT3 (5Tang J. Gary J.D. Clarke S. Herschman H.R. PRMT 3, a type I protein arginine N-methyltransferase that differs from PRMT1 in its oligomerization, subcellular localization, substrate specificity, and regulation.J. Biol. Chem. 1998; 273: 16935-16945Google Scholar), CARM1 (PRMT4) (6Chen D. Ma H. Hong H. Koh S.S. Huang S.M. Schurter B.T. Aswad D.W. Stallcup M.R. Regulation of transcription by a protein methyltransferase.Science. 1999; 284: 2174-2177Google Scholar), and PRMT6 (7Frankel A. Yadav N. Lee J. Branscombe T.L. Clarke S. Bedford M.T. The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity.J. Biol. Chem. 2002; 277: 3537-3543Google Scholar); and one type II, PRMT5 (8Pollack B.P. Kotenko S.V. He W. Izotova L.S. Barnoski B.L. Pestka S. The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity.J. Biol. Chem. 1999; 274: 31531-31542Google Scholar). Recently, a new arginine methyltransferase was identified and by homology is likely a type I PRMT (9Gros L. Delaporte C. Frey S. Decesse J. de Saint-Vincent B.R. Cavarec L. Dubart A. Gudkov A.V. Jacquemin-Sablon A. Identification of new drug sensitivity genes using genetic suppressor elements: protein arginine N-methyltransferase mediates cell sensitivity to DNA-damaging agents.Cancer Res. 2003; 63: 164-171Google Scholar). Myelin basic proteins (MBPs) and histones are among the first proteins shown to contain dimethylated arginines (10Brostoff S. Eylar E.H. Localization of methylated arginine in the A1 protein from myelin.Proc. Natl. Acad. Sci. U. S. A. 1971; 68: 765-769Google Scholar, 11Paik W.K. Kim S. Protein methylase I. Purification and properties of the enzyme.J. Biol. Chem. 1968; 243: 2108-2114Google Scholar). MBP has been shown to contain sDMA, but the enzyme or the function of this post-translational modification remains unknown. Histones have been shown to be methylated by PRMT1 and CARM1 in vivo (12Strahl B.D. Briggs S.D. Brame C.J. Caldwell J.A. Koh S.S. Ma H. Cook R.G. Shabanowitz J. Hunt D.F. Stallcup M.R. Allis C.D. Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1.Curr. Biol. 2001; 11: 996-1000Google Scholar, 13Wang H. Huang Z.-Q. Xia L. Feng Q. Erdjument-Bromage H. Strahl B.D. Briggs S.D. Allis C.D. Wong J. Tempst P. Zhang Y. Methylation of histone H4 at arginine 3 facilitates transcriptional activation by nuclear hormone receptor.Science. 2001; 293: 853-857Google Scholar, 14Ma H. Baumann C.T. Li H. Strahl B.D. Rice R. Jelinek M.A. Aswad D.W. Allis C.D. Hager G.L. Stallcup M.R. Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter.Curr. Biol. 2001; 11: 1981-1985Google Scholar, 15Schurter B.T. Koh S.S. Chen D. Bunick G.J. Harp J.M. Hanson B.L. Henschen-Edman A. Mackay D.R. Stallcup M.R. Aswad D.W. Methylation of histone H3 by coactivator-associated arginine methyltransferase 1.Biochemistry. 2001; 40: 5747-5756Google Scholar, S. Methylation at arginine of histone H3 is to 2002; Scholar). methylation is thought to to the histone Allis C.D. the histone 2001; 293: Scholar). of dimethylated proteins proteins J. Aswad D.W. with to in proteins with RNA are recognized by arginine in Biol. Chem. Scholar, Q. vivo and in arginine methylation of RNA Biol. Scholar). have been and have been shown to to the RNA and of of Scholar, P. protein for 2001; Scholar, J. S. Identification of arginine of RNA to the Biol. Chem. 2001; Scholar). Thus, the methylation of these arginines be to or RNA but the for this has been lacking. has been shown that arginine methylation protein (2McBride A. Silver P. State of the Arg: protein methylation at arginines comes of age.Cell. 2001; 106: 5-8Google Scholar). was first shown by and Henry M.F. Silver P.A. Lee Arginine methylation facilitates the nuclear of 1998; that the of the yeast methyltransferase the nuclear of two and was shown that arginine methylation the of protein in nuclear and its is by arginine methylation in Biol. and the protein of J. Herschman H.R. The in subcellular Res. Scholar), J. Bedford M.T. S. RNA protein is an in vivo substrate for Biol. 2003; Scholar), and J. M.C. P. C. 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Protein a signal event in post-translational Sci. 1998; Scholar), proteins have been identified to be arginine-methylated. The of PRMT1 by the C. J. protein arginine methyltransferase to the of the in the type I J. Scholar), and arginine methylation of has been shown to be required for J. W. Schurter B.T. Herschman H.R. Arginine methylation of 2001; Scholar). the methylation of peptides with M.T. A. Clarke S. P. S. Arginine methylation the of to homology 3, but Biol. Chem. Scholar). the four arginine antibodies to purify protein The proteins were identified by LC/MS/MS, and the protein were for that the used to the We the identification of over 200 proteins that are putatively arginine-methylated. These include transcription and polyadenylation cytoskeleton as as proteins in signal and DNA repair. These the role of arginine methylation in many cellular processes. SYM10 and ASYM24 have been previously J. Bedford M.T. S. RNA protein is an in vivo substrate for Biol. 2003; Scholar, J. M.C. P. C. S. methylation is required for the of in and pre-mRNA Biol. 2002; and are by SYM11 and ASYM25 were generated by with the peptides and respectively. antibodies were generated by using with peptides coupled to were from and in a containing 20 and methylated proteins were from the cell using of the methyl-specific antibody coupled to of protein with and the proteins were with of containing proteins were and identified using and of proteins were or with for at were on a with a to an was coupled by reverse-phase at a of 200 with a of and is and is in All were liquid chromatography was using a and two for sensitivity of the proteins were by and by to were with and on a using as the in a dimethylated cellular were with SYM10 is an antibody that generated previously have shown that SYM10 sDMA aDMA, at of J. M.C. P. C. S. methylation is required for the of in and pre-mRNA Biol. 2002; Scholar). analysis by the SYM10 as at least preferentially in a is with the fact that SYM10 recognize a from MBP that a J. M.C. P. C. S. methylation is required for the of in and pre-mRNA Biol. 2002; Scholar). The for SYM10 in PRMT5 small that PRMT5 is an enzyme that to the SYM10 J. M.C. P. C. S. methylation is required for the of in and pre-mRNA Biol. 2002; Scholar). We have shown previously that one of the complexes by SYM10 was the include proteins and J. M.C. P. C. S. methylation is required for the of in and pre-mRNA Biol. 2002; Scholar). the proteins in the SYM10 identified as an protein J. M.C. P. C. S. methylation is required for the of in and pre-mRNA Biol. 2002; Scholar). was generated and peptides as by the for SYM10 and SYM11 each recognize specific protein as by The are but as the proteins are both recognized by these antibodies ASYM24 was generated by using the as an as previously J. Bedford M.T. S. RNA protein is an in vivo substrate for Biol. 2003; Scholar). ASYM24 aDMA and was shown to recognize an protein J. Bedford M.T. S. RNA protein is an in vivo substrate for Biol. 2003; Scholar). The for ASYM24 in that the major enzyme that to the ASYM24 is PRMT1 J. Bedford M.T. S. RNA protein is an in vivo substrate for Biol. 2003; Scholar). ASYM25 was generated by with the ASYM25 is and has a different specificity than ASYM24 as by least two were with cell extracts using each of the was using the protein The protein complexes were with the The proteins were with and the peptides were and identified by LC/MS/MS, is a mass to the analysis of protein the of by were identified by using mass by a in The mass were using and were to a mass with for to the for These results were using the Protein at of and the a than were All proteins that were using this were identified using LC/MS/MS, this was used for the of the were using the for of with a mass of and a mass of as as for two protein was by was in the with protein and was identified in than one the of unique peptides was than or the two by than The identified proteins were to or putative that were previously to be methylated are with in The proteins that contain the the for antibodies and are likely to contains sDMA or aDMA in in The proteins that are of are likely identified with the SYM10 antibody in a new of the purified proteins with SYM10 and SYM11 proteins or with pre-mRNA I and The and small nuclear proteins and contain that have been shown to contain sDMA H. J. A. de L. R. The of the proteins and contain symmetrical a major for Biol. Chem. Scholar, H. L. de U. R. of arginine in protein and the protein and with the 2001; and are for SYM10 J. M.C. P. C. S. methylation is required for the of in and pre-mRNA Biol. 2002; and for The of proteins and and were that are likely purified with SYM10 proteins were and in a of 2003; Scholar). The and proteins and were likely with the in the new Biol. 2001; Scholar). and contain that are for arginine methylation and SYM10 and SYM11 I and identified with the SYM11 antibody in a new The SYM10 and SYM11 antibodies purified the a of proteins and H. J.M. new mediates an 11: Scholar, S. R. localization, and Biol. 2003; Scholar, Y. E.H. of a Biol. Scholar). The of that contain The for in or is in human liposarcoma A. P. N. D. of to a novel protein in human Scholar). The protein has been shown to function as a and is in DNA A. S. A. The transcription interacts with the Biol. Chem. 1998; 273: Scholar, N. A. S. L. D. L. in results in and of and Scholar). was shown to be a substrate of PRMT1 J. Bedford M.T. identified as an arginine methyltransferase substrate using protein 2002; and shown to contain aDMA J. W.J. S. of arginine dimethylated peptides by mass in Chem. 2003; Scholar). Thus, likely a protein for with was the Ewing sarcoma protein J. C.T. Ewing sarcoma a transcription that the by for Natl. Acad. Sci. U. S. A. Scholar). The protein has been shown to contain dimethylated has been shown the modification was or H. on cell and arginine methylation of sarcoma Biol. Chem. 2001; Scholar). that contains sDMA of its in SYM10 is the for and this nuclear is with and and Biol. 2002; Scholar). We and have shown that the of are dimethylated on arginines J. M.C. P. C. S. methylation is required for the of in and pre-mRNA Biol. 2002; Scholar, M.D. methylation nuclear 2002; Scholar). RNA containing were purified with ASYM25 of these with the a RNA with Biol. Chem. 2002; 277: Scholar). proteins were identified the substrate in has been shown to function in of RNA J. Bedford M.T. S. RNA protein is an in vivo substrate for Biol. 2003; Scholar). protein was purified with ASYM24 that contains The of interact with and to the L. J. N. interacts with a novel of and J. 2001; identified with the ASYM25 antibody in a new identified with the ASYM24 antibody in a new protein that was by SYM10 but SYM11 was the cleavage and polyadenylation specificity the and The proteins and as as were purified A. N. The the function of and proteins in Biol. 2001; Scholar). a protein of has that are likely the for and the components are likely proteins U. D. W. pre-mRNA cleavage is to proteins and be in from 1998; Scholar). has been shown to be dimethylated by CARM1 at arginine and is an for SYM10 J. Bedford M.T. identified as an arginine methyltransferase substrate using protein 2002; Scholar). Thus, and are likely purified as proteins with the SYM11 purified the is a ASYM24 and ASYM25 purified proteins and components and The role of arginine methylation in transcriptional is with histones a major of protein-arginine methyltransferases the histones contain RG-rich to and histones were SYM11 purified transcriptional proteins in of proteins histone I) J. The of histone 2003; 274: and methyltransferase were identified II) Q. H. Erdjument-Bromage H. Tempst P. Zhang Y. Methylation of is mediated by a new of a Biol. 2002; Scholar). proteins with were identified II) protein a role in transcriptional A. Identification and characterization of a of mammalian Biol. 1998; Scholar, S. N. mammalian protein with specific for 1999; Scholar), and the transcription protein protein in transcriptional and a is in the of RNA II H. Kim H. D. protein to RNA 1999; Scholar), were purified with transcription were identified the basic protein and and protein the and was identified with SYM11 and ASYM24 that contains both The of has that are likely for SYM10 to a to an to cell B.L. J.D. P. P. J.A. of an in the Natl. Acad. Sci. U. S. A. 2003; Scholar, J. J. of the transcription in cell to Mol. 2003; Scholar). The protein was identified by LC/MS/MS, and the of in its that is a of The function of is but is a protein with an protein and interact with and the arginine methylation of Biol. Chem. Scholar). The of in of to type W. type by a in of 2001; 293: Scholar). Thus, arginine methylation the transcriptional and were identified with the the receptor and the II receptor were purified by SYM10 the receptor was identified with SYM11 and were identified with ASYM25 This analysis is the first that contain dimethylated and the of that the were recognized by the The receptor is in the of of and in the from that 2003; Scholar). The II receptor has and its in with L. E.H. N. A. and of 2002; Scholar). cell that were identified include is an receptor that of the of the and a novel of 1998; Scholar). The receptor was identified with and contains receptor was identified with The receptor is required for of the asymmetrical of a cell an a Biol. 2003; Scholar). was identified with SYM10 and a was identified with ASYM24 proteins or with proteins were identified the substrate the 3 the from ataxia telangiectasia protein and is an protein that in cell M.T. J.D. M.R. a substrate with and to and to Biol. Chem. 1996; 271: Scholar). contains a putative and a and has been shown to with of activation and cell by and Biol. Chem. 2003; Scholar). The of in and that were likely contains RG-rich and was identified with is to protein or C. C. R. J.D. The and Biol. Chem. 2003; Scholar). is a that is in DNA signal the of that was A. S. Y. L. S. S. ataxia telangiectasia with a to Scholar). Protein is an identified with The is to be in to the and was identified with a II and has been shown to be to complexes J. of the II to the role of Biol. 2001; Scholar). is an protein purified with ASYM24 was identified as a of and has been shown to novel proteins by the Biol. Chem. 2003; Scholar). proteins in were protein and J. Res. 2003; Scholar). These proteins are as are of The identification of the receptor with ASYM25 that arginine methylation a role in cell The of the Biol. was purified by using The to DNA and nuclear are the cellular to DNA Biol. Scholar). The of in that an for ASYM25 and that and are proteins with ASYM25 and proteins type II type and and were purified is to that of the components are but the of these proteins likely for the the have identified over 200 proteins that contain RG-rich and are putative of protein-arginine The identification and of proteins to contain dimethylated arginines such as EWS, TLS, and of these proteins are with RNA and contain RG-rich Gary and Clarke (1Gary J.D. Clarke S. RNA and protein interactions modulated by protein arginine methylation.Prog. Nucleic Acid Res. Mol. Biol. 1998; 61: 65-131Google for PRMT by using with sequences. The was from the methylation of basic and MBP (1Gary J.D. Clarke S. RNA and protein interactions modulated by protein arginine methylation.Prog. Nucleic Acid Res. Mol. Biol. 1998; 61: 65-131Google Scholar). identified mammalian EWS, TLS, and Thus, the major of putative was using antibodies that are specific for sDMA or aDMA, were to the of proteins antibody was with unique were to proteins that be by using a The of proteins and in SYM10 and SYM11 the specificity of these antibodies for proteins in cellular has been that the for to of arginine methylation that occurs in the cell Q. vivo and in arginine methylation of RNA Biol. Scholar). These proteins contain of and that have been to contain dimethylated arginines. The fact that the SYM10 and SYM11 a the specificity of the antibody for sDMA and aDMA or RG-rich We have the ASYM24 and ASYM25 antibodies to recognize the of proteins as as the proteins and protein have identified the cell E.H. J.M. a novel of and and Li R. S. cellular proteins that to but Natl. Acad. Sci. U. S. A. Scholar), two proteins to contain This that the antibodies that generated recognize a of methylated proteins the of methylated peptides to were recognized by ASYM24 in an J. Bedford M.T. S. RNA protein is an in vivo substrate for Biol. 2003; Scholar). the mass the and PRMT5 complexes in the SYM10 with and PRMT5 were identified in SYM10 in HeLa as shown previously J. M.C. P. C. S. methylation is required for the of in and pre-mRNA Biol. 2002; Scholar). has been shown that complexes in HeLa cell Frey M.R. and or J. 1998; 63: Scholar). Thus, the proteins that were identified the be contain and are by the are in a that contains DMA, or are proteins that were the The of that of the proteins were recognized by the is that of the proteins are but the of in a for The identification of many proteins in the such as the pre-mRNA and polyadenylation to that is in the function of that The identification of proteins in pre-mRNA and transcription was (2McBride A. Silver P. State of the Arg: protein methylation at arginines comes of age.Cell. 2001; 106: 5-8Google Scholar). The identification of the the polyadenylation and proteins in DNA and cell was The role of sDMA in is and has been as a signal for to the W.J. S. S. A. SMN, the of the preferentially to protein 2001; Scholar). of cell extracts with SYM10 or with methylase pre-mRNA J. Bedford M.T. S. RNA protein is an in vivo substrate for Biol. 2003; Scholar). The identification of and the proteins a new of of by arginine The role of arginine methylation in transcription has been the identification of CARM1 as a coactivator (6Chen D. Ma H. Hong H. Koh S.S. Huang S.M. Schurter B.T. Aswad D.W. Stallcup M.R. Regulation of transcription by a protein methyltransferase.Science. 1999; 284: 2174-2177Google Scholar). The in of the The identification of transcription and as as the transcription and the transcription protein new of transcription by arginine The sDMA and transcription has been S.E. J. C. Cook Lee Pestka S. A. C. of transcription by the type II arginine methyltransferase 2002; Scholar); the of PRMT5 were arginine methylation the and transcription an of has been for J. S. P. Methylation of its with RNA II and transcriptional 2003; 11: Scholar). The of in to that these proteins are likely to be dimethylated on arginines. The of RG-rich that this be the be to the methylation with the or with the of the The of the and by SYM10 that a protein the contains sDMA U. D. W. pre-mRNA cleavage is to proteins and be in from 1998; Scholar). The of in the that this protein is putatively methylated by type II The fact that with proteins W.J. S. S. A. SMN, the of the preferentially to protein 2001; and has been the Biol. 2001; 11: that the localization, and function be by the The of the Biol. was purified by using the was purified with The to DNA and nuclear are the cellular to DNA Biol. Scholar), and the is in DNA A. S. Y. L. S. S. ataxia telangiectasia with a to Scholar). The of in that an for ASYM25 and that and are The of proteins in DNA that arginine methylation have a role in this cellular Arginine methylation the of DNA or protein DNA the identification of proteins containing to on new for this post-translational The methylation of protein on the of putative methylated proteins have to be and have to be The the of arginine methylation in pre-mRNA splicing, protein receptor transcription, DNA and the We and for analysis and Bedford for the We and for with the mass were from

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