Protein arginine methyltransferase 5 explained

Protein arginine N-methyltransferase 5 is an enzyme that in humans is encoded by the PRMT5 gene.^{[1] [2]} PRMT5 symmetrically dimethylates H2AR3, H4R3, H3R2, and H3R8 in vivo, all of which are linked to a range of transcriptional regulatory events.^[3]

PRMT5 is a highly conserved arginine methyltransferase that translocated from the cytoplasm to the nucleus at embryonic day ~E8.5, and during preimplantation development at the ~4-cell stage.^[4]

Interactions

Protein arginine methyltransferase 5 has been shown to interact with:

• CLNS1A,^{[5] [6] [7]}
• Janus kinase 2,^[8]
• SNRPD3,^[6]
• SUPT5H,^[9]
• MEP50,^[10]
• RIOK1, ^[11]
• COPR5.

PRMT5 has been shown to interact with CLNS1A, RIOK1 and COPR5 through an interface created by a shallow groove located on the TIM barrel domain of PRMT5 and the consensus sequence GQF[D/E]DA[E/D] located in the terminal regions of the adaptor proteins.^[12] The characterisation of the interactions occurring in the binding groove between PRMT5 and peptides derived from the adaptor proteins lead to development of protein-protein interaction (PPI) inhibitors, modulating binding between PRMT5 and the adaptor proteins.^{[13] [14]} Furthermore, Asberry and co-workers synthesised the first-in-class small molecule inhibitor of the PPI between PRMT5 and MEP50.^[15] The PPI inhibitors complement a plethora of compounds directly suppressing the enzymatic activity of PRMT5.^[16]

References

Further reading

• Schwärzler A, Kreienkamp HJ, Richter D . Interaction of the somatostatin receptor subtype 1 with the human homolog of the Shk1 kinase-binding protein from yeast. . J. Biol. Chem. . 275 . 13 . 9557–62 . 2000 . 10734105 . 10.1074/jbc.275.13.9557 . free .
• Rho J, Choi S, Seong YR, Cho WK, Kim SH, Im DS . Prmt5, which forms distinct homo-oligomers, is a member of the protein-arginine methyltransferase family. . J. Biol. Chem. . 276 . 14 . 11393–401 . 2001 . 11152681 . 10.1074/jbc.M008660200 . free.
• Brahms H, Meheus L, de Brabandere V, Fischer U, Lührmann R . Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B' and the Sm-like protein LSm4, and their interaction with the SMN protein. . RNA . 7 . 11 . 1531–42 . 2001 . 11720283 . 1370196 . 10.1017/S135583820101442X .
• Meister G, Eggert C, Bühler D, Brahms H, Kambach C, Fischer U . Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln. . Curr. Biol. . 11 . 24 . 1990–4 . 2002 . 11747828 . 10.1016/S0960-9822(01)00592-9 . 11858/00-001M-0000-0012-F501-7 . 14742376 . free .
• Fabbrizio E, El Messaoudi S, Polanowska J, Paul C, Cook JR, Lee JH, Negre V, Rousset M, Pestka S, Le Cam A, Sardet C . Negative regulation of transcription by the type II arginine methyltransferase PRMT5. . EMBO Rep. . 3 . 7 . 641–5 . 2003 . 12101096 . 1084190 . 10.1093/embo-reports/kvf136 .
• Jiang LQ, Wen SJ, Wang HY, Chen LY . Screening the proteins that interact with calpain in a human heart cDNA library using a yeast two-hybrid system. . Hypertens. Res. . 25 . 4 . 647–52 . 2003 . 12358155 . 10.1291/hypres.25.647 . free .
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J . Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. . Nat. Biotechnol. . 21 . 5 . 566–9 . 2004 . 12665801 . 10.1038/nbt810 . 23783563 .
• Pal S, Yun R, Datta A, Lacomis L, Erdjument-Bromage H, Kumar J, Tempst P, Sif S . mSin3A/histone deacetylase 2- and PRMT5-containing Brg1 complex is involved in transcriptional repression of the Myc target gene cad. . Mol. Cell. Biol. . 23 . 21 . 7475–87 . 2003 . 14559996 . 207647 . 10.1128/MCB.23.21.7475-7487.2003 .
• Yanagida M, Hayano T, Yamauchi Y, Shinkawa T, Natsume T, Isobe T, Takahashi N . Human fibrillarin forms a sub-complex with splicing factor 2-associated p32, protein arginine methyltransferases, and tubulins alpha 3 and beta 1 that is independent of its association with preribosomal ribonucleoprotein complexes. . J. Biol. Chem. . 279 . 3 . 1607–14 . 2004 . 14583623 . 10.1074/jbc.M305604200 . free .
• Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, Metalnikov P, O'Donnell P, Taylor P, Taylor L, Zougman A, Woodgett JR, Langeberg LK, Scott JD, Pawson T . Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. . Curr. Biol. . 14 . 16 . 1436–50 . 2004 . 15324660 . 10.1016/j.cub.2004.07.051 . 2371325 . free . 2004CBio...14.1436J .
• Miranda TB, Khusial P, Cook JR, Lee JH, Gunderson SI, Pestka S, Zieve GW, Clarke S . Spliceosome Sm proteins D1, D3, and B/B' are asymmetrically dimethylated at arginine residues in the nucleus. . Biochem. Biophys. Res. Commun. . 323 . 2 . 382–7 . 2004 . 15369763 . 10.1016/j.bbrc.2004.08.107 .
• Pal S, Vishwanath SN, Erdjument-Bromage H, Tempst P, Sif S . Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes. . Mol. Cell. Biol. . 24 . 21 . 9630–45 . 2004 . 15485929 . 522266 . 10.1128/MCB.24.21.9630-9645.2004 .

Notes and References

1. Gilbreth M, Yang P, Bartholomeusz G, Pimental RA, Kansra S, Gadiraju R, Marcus S . Negative regulation of mitosis in fission yeast by the shk1 interacting protein skb1 and its human homolog, Skb1Hs . Proc Natl Acad Sci U S A . 95 . 25 . 14781–6 . Jan 1999 . 9843966 . 24526 . 10.1073/pnas.95.25.14781 . free .
2. Web site: Entrez Gene: PRMT5 protein arginine methyltransferase 5.
3. Stopa N, Krebs JE, Shechter D . The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond . Cellular and Molecular Life Sciences . 72 . 11 . 2041–59 . June 2015 . 25662273 . 4430368 . 10.1007/s00018-015-1847-9 .
4. Kim S, Gunesdogan, U, Zylicz JJ, Hackett, JA, Cougot, D, Bao, S, Lee, C, Dietmann, S, Allen, GE, Sngupta, R, Surani MA . PRMT5 Protects Genomic Integrity during Global DNA Demethylation in Primordial Germ Cells and Preimplantation Embryos . Molecular Cell . 56 . 4 . 564–579 . Nov 2014 . 10.1016/j.molcel.2014.10.003 . 25457166 . 4250265 .
5. Krapivinsky G, Pu W, Wickman K, Krapivinsky L, Clapham DE . pICln binds to a mammalian homolog of a yeast protein involved in regulation of cell morphology . J. Biol. Chem. . 273 . 18 . 10811–4 . May 1998 . 9556550 . 10.1074/jbc.273.18.10811. free .
6. Friesen WJ, Paushkin S, Wyce A, Massenet S, Pesiridis GS, Van Duyne G, Rappsilber J, Mann M, Dreyfuss G . The methylosome, a 20S complex containing JBP1 and pICln, produces dimethylarginine-modified Sm proteins . Mol. Cell. Biol. . 21 . 24 . 8289–300 . Dec 2001 . 11713266 . 99994 . 10.1128/MCB.21.24.8289-8300.2001 .
7. Krzyzanowski A, Gasper R, Adihou H, 't Hart P, Waldmann H . Biochemical Investigation of the Interaction of pICln, RioK1 and COPR5 with the PRMT5-MEP50 Complex . ChemBioChem . Feb 2021 . 22 . 11 . 1908–1914 . 10.1002/cbic.202100079 . 33624332 . 8252068 . free .
8. Pollack BP, Kotenko SV, He W, Izotova LS, Barnoski BL, Pestka S . The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity . J. Biol. Chem. . 274 . 44 . 31531–42 . Oct 1999 . 10531356 . 10.1074/jbc.274.44.31531. free .
9. Richard Gaynor. Kwak YT, Guo J, Prajapati S, Park KJ, Surabhi RM, Miller B, Gehrig P, Gaynor RB . Methylation of SPT5 regulates its interaction with RNA polymerase II and transcriptional elongation properties . Mol. Cell . 11 . 4 . 1055–66 . Apr 2003 . 12718890 . 10.1016/s1097-2765(03)00101-1. free .
10. Friesen WJ, Wyce A, Paushkin S, Abel L, Rappsilber J, Mann M, Dreyfuss G . A novel WD repeat protein component of the methylosome binds Sm proteins . J. Biol. Chem. . 277 . 10 . 8243–7 . Mar 2002 . 11756452 . 10.1074/jbc.M109984200 . free .
11. Guderian G, Peter C, Wiesner J, Sickmann A, Schulze-Osthoff K, Fischer U, Grimmler M . RioK1, a new interactor of protein arginine methyltransferase 5 (PRMT5), competes with pICln for binding and modulates PRMT5 complex composition and substrate specificity . J Biol Chem . 286 . 3 . 1976–86 . Jan 2011 . 21081503 . 3023494 . 10.1074/jbc.M110.148486. free .
12. Mulvaney KM, Blomquis C, Acharya N, Li R, O'Keefe M, Ranaghan M, Stokes M, Nelson AJ, Jain SS, Columbus J, Bozal FK, Skepner A, Raymond D, McKinney DC, Freyzon Y, Baidi Y, Porter D, Ianari A, McMillan B, Sellers WR . Aug 2020 . Molecular basis for substrate recruitment to the PRMT5 methylosome (preprint) . 10.1101/2020.08.22.256347.
13. McKinney DC, McMillan BJ, Ranaghan MJ, Moroco JA, Brousseau M, Mullin-Bernstein Z, O'Keefe M, McCarren P, Mesleh MF, Mulvaney KM, Robinson F, Singh R, Bajrami B, Wagner FF, Hilgraf R, Drysdale MJ, Campbell AJ, Skepner A, Timm DE, Porter D, Kaushik VK, Sellers WR, Ianari A . Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction . Journal of Medicinal Chemistry . 64 . 15 . 11148–11168 . August 2021 . 34342224 . 10.1021/acs.jmedchem.1c00507 . 236884799 . 9036822 .
14. Krzyzanowski A, Esser LM, Willaume A, Prudent R, Peter C, 't Hart P, Waldmann H . Development of Macrocyclic PRMT5-Adaptor Protein Interaction Inhibitors . J. Med. Chem. . Nov 2022 . 65 . 22 . 15300–15311 . 10.1021/acs.jmedchem.2c01273 . 36378254 . free . 9706563 .
15. Asberry AM, Cai X, Deng X, Santiago U, Liu S, Sims HS, Liang W, Xu X, Wan J, Jiang W, Camacho CJ, Dai M, Hu CD . Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors . Journal of Medicinal Chemistry . 65 . 20 . 13793–13812 . October 2022 . 36206451 . 10.1021/acs.jmedchem.2c01000 . 252758808 . 11167723 .
16. Fu S, Zheng Q, Zhang D, Lin C, Ouyang L, Zhang J, Chen L . Medicinal chemistry strategies targeting PRMT5 for cancer therapy . European Journal of Medicinal Chemistry . 244 . 114842 . December 2022 . 36274274 . 10.1016/j.ejmech.2022.114842 . 252956172 .