| Structural highlights
5lgq is a 8 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Activity: | Type I protein arginine methyltransferase, with EC number 2.1.1.319 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[CARM1_MOUSE] Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activates transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [PABP1_HUMAN] Binds the poly(A) tail of mRNA. May be involved in cytoplasmic regulatory processes of mRNA metabolism such as pre-mRNA splicing. Its function in translational initiation regulation can either be enhanced by PAIP1 or repressed by PAIP2. Can probably bind to cytoplasmic RNA sequences other than poly(A) in vivo. Involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain. Involved in regulation of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons; for the recognition of premature termination codons (PTC) and initiation of NMD a competitive interaction between UPF1 and PABPC1 with the ribosome-bound release factors is proposed.[18] [19]
Publication Abstract from PubMed
Coactivator associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family and methylates a range of proteins in eukaryotic cells. Overexpression of CARM1 is implicated in a number of cancers, and it is therefore seen as a potential therapeutic target. Peptide sequences derived from the well-defined CARM1 substrate poly(A)-binding protein 1 (PABP1) were covalently linked to an adenosine moiety as in the AdoMet cofactor to generate transition state mimics. These constructs were found to be potent CARM1 inhibitors and also formed stable complexes with the enzyme. High-resolution crystal structures of CARM1 in complex with these compounds confirm a mode of binding that is indeed reflective of the transition state at the CARM1 active site. Given the transient nature of PRMT-substrate complexes, such transition state mimics represent valuable chemical tools for structural studies aimed at deciphering the regulation of arginine methylation mediated by the family of arginine methyltransferases.
Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1.,van Haren MJ, Marechal N, Troffer-Charlier N, Cianciulli A, Sbardella G, Cavarelli J, Martin NI Proc Natl Acad Sci U S A. 2017 Mar 22. pii: 201618401. doi:, 10.1073/pnas.1618401114. PMID:28330993[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, Aswad DW, Stallcup MR. Regulation of transcription by a protein methyltransferase. Science. 1999 Jun 25;284(5423):2174-7. PMID:10381882
- ↑ Schurter BT, Koh SS, Chen D, Bunick GJ, Harp JM, Hanson BL, Henschen-Edman A, Mackay DR, Stallcup MR, Aswad DW. Methylation of histone H3 by coactivator-associated arginine methyltransferase 1. Biochemistry. 2001 May 15;40(19):5747-56. PMID:11341840
- ↑ Xu W, Chen H, Du K, Asahara H, Tini M, Emerson BM, Montminy M, Evans RM. A transcriptional switch mediated by cofactor methylation. Science. 2001 Dec 21;294(5551):2507-11. Epub 2001 Nov 8. PMID:11701890 doi:10.1126/science.1065961
- ↑ Chen SL, Loffler KA, Chen D, Stallcup MR, Muscat GE. The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2. J Biol Chem. 2002 Feb 8;277(6):4324-33. Epub 2001 Nov 16. PMID:11713257 doi:http://dx.doi.org/10.1074/jbc.M109835200
- ↑ Koh SS, Li H, Lee YH, Widelitz RB, Chuong CM, Stallcup MR. Synergistic coactivator function by coactivator-associated arginine methyltransferase (CARM) 1 and beta-catenin with two different classes of DNA-binding transcriptional activators. J Biol Chem. 2002 Jul 19;277(29):26031-5. Epub 2002 Apr 30. PMID:11983685 doi:http://dx.doi.org/10.1074/jbc.M110865200
- ↑ Lee YH, Koh SS, Zhang X, Cheng X, Stallcup MR. Synergy among nuclear receptor coactivators: selective requirement for protein methyltransferase and acetyltransferase activities. Mol Cell Biol. 2002 Jun;22(11):3621-32. PMID:11997499
- ↑ Yadav N, Lee J, Kim J, Shen J, Hu MC, Aldaz CM, Bedford MT. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6464-8. Epub 2003 May 19. PMID:12756295 doi:http://dx.doi.org/10.1073/pnas.1232272100
- ↑ Lee YH, Campbell HD, Stallcup MR. Developmentally essential protein flightless I is a nuclear receptor coactivator with actin binding activity. Mol Cell Biol. 2004 Mar;24(5):2103-17. PMID:14966289
- ↑ An W, Kim J, Roeder RG. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell. 2004 Jun 11;117(6):735-48. PMID:15186775 doi:10.1016/j.cell.2004.05.009
- ↑ Covic M, Hassa PO, Saccani S, Buerki C, Meier NI, Lombardi C, Imhof R, Bedford MT, Natoli G, Hottiger MO. Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-kappaB-dependent gene expression. EMBO J. 2005 Jan 12;24(1):85-96. Epub 2004 Dec 16. PMID:15616592 doi:http://dx.doi.org/10.1038/sj.emboj.7600500
- ↑ Teyssier C, Ou CY, Khetchoumian K, Losson R, Stallcup MR. Transcriptional intermediary factor 1alpha mediates physical interaction and functional synergy between the coactivator-associated arginine methyltransferase 1 and glucocorticoid receptor-interacting protein 1 nuclear receptor coactivators. Mol Endocrinol. 2006 Jun;20(6):1276-86. Epub 2005 Dec 1. PMID:16322096 doi:10.1210/me.2005-0393
- ↑ Cheng D, Cote J, Shaaban S, Bedford MT. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol Cell. 2007 Jan 12;25(1):71-83. PMID:17218272 doi:http://dx.doi.org/10.1016/j.molcel.2006.11.019
- ↑ Yue WW, Hassler M, Roe SM, Thompson-Vale V, Pearl LH. Insights into histone code syntax from structural and biochemical studies of CARM1 methyltransferase. EMBO J. 2007 Oct 17;26(20):4402-12. Epub 2007 Sep 20. PMID:17882261
- ↑ Yadav N, Cheng D, Richard S, Morel M, Iyer VR, Aldaz CM, Bedford MT. CARM1 promotes adipocyte differentiation by coactivating PPARgamma. EMBO Rep. 2008 Feb;9(2):193-8. doi: 10.1038/sj.embor.7401151. Epub 2008 Jan 11. PMID:18188184 doi:http://dx.doi.org/10.1038/sj.embor.7401151
- ↑ Feng Q, He B, Jung SY, Song Y, Qin J, Tsai SY, Tsai MJ, O'Malley BW. Biochemical control of CARM1 enzymatic activity by phosphorylation. J Biol Chem. 2009 Dec 25;284(52):36167-74. doi: 10.1074/jbc.M109.065524. Epub, 2009 Oct 20. PMID:19843527 doi:http://dx.doi.org/10.1074/jbc.M109.065524
- ↑ Kim D, Lee J, Cheng D, Li J, Carter C, Richie E, Bedford MT. Enzymatic activity is required for the in vivo functions of CARM1. J Biol Chem. 2010 Jan 8;285(2):1147-52. Epub 2009 Nov 5. PMID:19897492 doi:http://dx.doi.org/M109.035865
- ↑ Kuhn P, Chumanov R, Wang Y, Ge Y, Burgess RR, Xu W. Automethylation of CARM1 allows coupling of transcription and mRNA splicing. Nucleic Acids Res. 2011 Apr;39(7):2717-26. doi: 10.1093/nar/gkq1246. Epub 2010, Dec 7. PMID:21138967 doi:http://dx.doi.org/10.1093/nar/gkq1246
- ↑ Grosset C, Chen CY, Xu N, Sonenberg N, Jacquemin-Sablon H, Shyu AB. A mechanism for translationally coupled mRNA turnover: interaction between the poly(A) tail and a c-fos RNA coding determinant via a protein complex. Cell. 2000 Sep 29;103(1):29-40. PMID:11051545
- ↑ Singh G, Rebbapragada I, Lykke-Andersen J. A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay. PLoS Biol. 2008 Apr 29;6(4):e111. doi: 10.1371/journal.pbio.0060111. PMID:18447585 doi:10.1371/journal.pbio.0060111
- ↑ van Haren MJ, Marechal N, Troffer-Charlier N, Cianciulli A, Sbardella G, Cavarelli J, Martin NI. Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1. Proc Natl Acad Sci U S A. 2017 Mar 22. pii: 201618401. doi:, 10.1073/pnas.1618401114. PMID:28330993 doi:http://dx.doi.org/10.1073/pnas.1618401114
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