4y2h

Structural highlights

Function

ANM6_HUMAN Arginine methyltransferase that can catalyze the formation of both omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA), with a strong preference for the formation of aDMA. Preferentially methylates arginyl residues present in a glycine and arginine-rich domain and displays preference for monomethylated substrates. Specifically mediates the asymmetric dimethylation of histone H3 'Arg-2' to form H3R2me2a. H3R2me2a represents a specific tag for epigenetic transcriptional repression and is mutually exclusive with methylation on histone H3 'Lys-4' (H3K4me2 and H3K4me3). Acts as a transcriptional repressor of various genes such as HOXA2, THBS1 and TP53. Repression of TP53 blocks cellular senescence (By similarity). Also methylates histone H2A and H4 'Arg-3' (H2AR3me and H4R3me, respectively). Acts as a regulator of DNA base excision during DNA repair by mediating the methylation of DNA polymerase beta (POLB), leading to the stimulation of its polymerase activity by enhancing DNA binding and processivity. Methylates HMGA1. Regulates alternative splicing events. Acts as a transcriptional coactivator of a number of steroid hormone receptors including ESR1, ESR2, PGR and NR3C1. Promotes fasting-induced transcriptional activation of the gluconeogenic program through methylation of the CRTC2 transcription coactivator. May play a role in innate immunity against HIV-1 in case of infection by methylating and impairing the function of various HIV-1 proteins such as Tat, Rev and Nucleocapsid protein p7 (NC).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]}

See Also

• Histone methyltransferase 3D structures

References

1. ↑ Frankel A, Yadav N, Lee J, Branscombe TL, Clarke S, Bedford MT. The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity. J Biol Chem. 2002 Feb 1;277(5):3537-43. Epub 2001 Nov 27. PMID:11724789 doi:http://dx.doi.org/10.1074/jbc.M108786200
2. ↑ Miranda TB, Webb KJ, Edberg DD, Reeves R, Clarke S. Protein arginine methyltransferase 6 specifically methylates the nonhistone chromatin protein HMGA1a. Biochem Biophys Res Commun. 2005 Oct 28;336(3):831-5. PMID:16157300 doi:http://dx.doi.org/10.1016/j.bbrc.2005.08.179
3. ↑ Herrmann F, Lee J, Bedford MT, Fackelmayer FO. Dynamics of human protein arginine methyltransferase 1(PRMT1) in vivo. J Biol Chem. 2005 Nov 11;280(45):38005-10. Epub 2005 Sep 13. PMID:16159886 doi:http://dx.doi.org/10.1074/jbc.M502458200
4. ↑ El-Andaloussi N, Valovka T, Toueille M, Steinacher R, Focke F, Gehrig P, Covic M, Hassa PO, Schar P, Hubscher U, Hottiger MO. Arginine methylation regulates DNA polymerase beta. Mol Cell. 2006 Apr 7;22(1):51-62. PMID:16600869 doi:http://dx.doi.org/10.1016/j.molcel.2006.02.013
5. ↑ Xie B, Invernizzi CF, Richard S, Wainberg MA. Arginine methylation of the human immunodeficiency virus type 1 Tat protein by PRMT6 negatively affects Tat Interactions with both cyclin T1 and the Tat transactivation region. J Virol. 2007 Apr;81(8):4226-34. Epub 2007 Jan 31. PMID:17267505 doi:http://dx.doi.org/10.1128/JVI.01888-06
6. ↑ Guccione E, Bassi C, Casadio F, Martinato F, Cesaroni M, Schuchlautz H, Luscher B, Amati B. Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature. 2007 Oct 18;449(7164):933-7. Epub 2007 Sep 26. PMID:17898714 doi:http://dx.doi.org/10.1038/nature06166
7. ↑ Hyllus D, Stein C, Schnabel K, Schiltz E, Imhof A, Dou Y, Hsieh J, Bauer UM. PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation. Genes Dev. 2007 Dec 15;21(24):3369-80. PMID:18079182 doi:http://dx.doi.org/10.1101/gad.447007
8. ↑ Iberg AN, Espejo A, Cheng D, Kim D, Michaud-Levesque J, Richard S, Bedford MT. Arginine methylation of the histone H3 tail impedes effector binding. J Biol Chem. 2008 Feb 8;283(6):3006-10. Epub 2007 Dec 11. PMID:18077460 doi:http://dx.doi.org/10.1074/jbc.C700192200
9. ↑ Lakowski TM, Frankel A. Kinetic analysis of human protein arginine N-methyltransferase 2: formation of monomethyl- and asymmetric dimethyl-arginine residues on histone H4. Biochem J. 2009 Jun 26;421(2):253-61. doi: 10.1042/BJ20090268. PMID:19405910 doi:10.1042/BJ20090268
10. ↑ Michaud-Levesque J, Richard S. Thrombospondin-1 is a transcriptional repression target of PRMT6. J Biol Chem. 2009 Aug 7;284(32):21338-46. doi: 10.1074/jbc.M109.005322. Epub 2009, Jun 9. PMID:19509293 doi:http://dx.doi.org/10.1074/jbc.M109.005322
11. ↑ Harrison MJ, Tang YH, Dowhan DH. Protein arginine methyltransferase 6 regulates multiple aspects of gene expression. Nucleic Acids Res. 2010 Apr;38(7):2201-16. doi: 10.1093/nar/gkp1203. Epub 2010, Jan 4. PMID:20047962 doi:http://dx.doi.org/10.1093/nar/gkp1203
12. ↑ Mitchell LH, Drew AE, Ribich SA, Rioux N, Swinger KK, Jacques SL, Lingaraj T, Boriack-Sjodin PA, Waters NJ, Wigle TJ, Moradei O, Jin L, Riera T, Porter-Scott M, Moyer MP, Smith JJ, Chesworth R, Copeland RA. Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound. ACS Med Chem Lett. 2015 Apr 6;6(6):655-9. doi: 10.1021/acsmedchemlett.5b00071., eCollection 2015 Jun 11. PMID:26101569 doi:http://dx.doi.org/10.1021/acsmedchemlett.5b00071