Protein arginine methyltransferase 5

Protein arginine N-methyltransferase 5 is an enzyme that in humans is encoded by the PRMT5 gene.^[5][6] PRMT5 symmetrically dimethylates H2AR3, H4R3, H3R2, and H3R8 in vivo, all of which are linked to a range of transcriptional regulatory events.^[7]

PRMT5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4GQB, 4X60, 4X61, 4X63, 5EML, 5FA5, 5EMJ, 5EMK, 5EMM, 5C9Z
Identifiers
Aliases	PRMT5, HRMT1L5, IBP72, JBP1, SKB1, SKB1Hs, Protein arginine methyltransferase 5, HSL7
External IDs	OMIM: 604045; MGI: 1351645; HomoloGene: 4454; GeneCards: PRMT5; OMA:PRMT5 - orthologs
EC number	2.1.1.321
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q11.2 Start 22,920,525 bp[1] End 22,929,408 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14|14 C2 Start 54,744,644 bp[2] End 54,754,982 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ventricular zone amniotic fluid ganglionic eminence gonad right uterine tube left ovary right ovary gastrocnemius muscle mucosa of transverse colon islet of Langerhans Top expressed in tail of embryo epiblast yolk sac maxillary prominence mandibular prominence genital tubercle otic vesicle somite primitive streak ventricular zone More reference expression data BioGPS More reference expression data
Gene ontology Molecular function methyltransferase activity transferase activity histone methyltransferase activity (H4-R3 specific) transcription corepressor activity methyl-CpG binding core promoter sequence-specific DNA binding protein binding protein heterodimerization activity ribonucleoprotein complex binding histone-arginine N-methyltransferase activity protein-arginine N-methyltransferase activity protein-arginine omega-N symmetric methyltransferase activity identical protein binding protein-containing complex binding E-box binding Cellular component cytoplasm cytosol Golgi apparatus nucleoplasm methylosome nucleus histone methyltransferase complex protein-containing complex Biological process regulation of mitotic nuclear division positive regulation of oligodendrocyte differentiation regulation of transcription, DNA-templated histone H4-R3 methylation rhythmic process DNA-templated transcription, termination negative regulation of cell differentiation peptidyl-arginine N-methylation endothelial cell activation circadian regulation of gene expression transcription, DNA-templated spliceosomal snRNP assembly liver regeneration methylation peptidyl-arginine methylation regulation of ERK1 and ERK2 cascade regulation of DNA methylation cell population proliferation Golgi ribbon formation protein methylation negative regulation of nucleic acid-templated transcription positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway regulation of signal transduction by p53 class mediator peptidyl-arginine methylation, to symmetrical-dimethyl arginine chromatin organization histone arginine methylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10419 27374 Ensembl ENSG00000100462 ENSMUSG00000023110 UniProt O14744 Q8CIG8 RefSeq (mRNA) NM_001039619 NM_001282953 NM_001282954 NM_001282955 NM_001282956 NM_006109 NM_013768 NM_001313906 NM_001313907 RefSeq (protein) NP_001034708 NP_001269882 NP_001269883 NP_001269884 NP_001269885 NP_006100 NP_001300835 NP_001300836 NP_038796 Location (UCSC) Chr 14: 22.92 – 22.93 Mb Chr 14: 54.74 – 54.75 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[8]

Interactions

Protein arginine methyltransferase 5 has been shown to interact with:

• CLNS1A,^{[9][10][11][12]}
• Janus kinase 2,^[13]
• SNRPD3,^[11]
• SUPT5H,^[14]
• MEP50,^[9]
• RIOK1, ^[15][12]
• COPR5.^[12]

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][16] 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.^[17][18] Furthermore, Asberry and co-workers synthesised the first-in-class small molecule inhibitor of the PPI between PRMT5 and MEP50.^[19] The PPI inhibitors complement a plethora of compounds directly suppressing the enzymatic activity of PRMT5.^[20]

References

1. GRCh38: Ensembl release 89: ENSG00000100462 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000023110 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Gilbreth M, Yang P, Bartholomeusz G, et al. (Jan 1999). "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. doi:10.1073/pnas.95.25.14781. PMC 24526. PMID 9843966.
6. "Entrez Gene: PRMT5 protein arginine methyltransferase 5".
7. Stopa N, Krebs JE, Shechter D (June 2015). "The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond". Cellular and Molecular Life Sciences. 72 (11): 2041–59. doi:10.1007/s00018-015-1847-9. PMC 4430368. PMID 25662273.
8. Kim S, Gunesdogan, U, et al. (Nov 2014). "PRMT5 Protects Genomic Integrity during Global DNA Demethylation in Primordial Germ Cells and Preimplantation Embryos". Molecular Cell. 56 (4): 564–579. doi:10.1016/j.molcel.2014.10.003. PMC 4250265. PMID 25457166.
9. Friesen WJ, Wyce A, Paushkin S, et al. (Mar 2002). "A novel WD repeat protein component of the methylosome binds Sm proteins". J. Biol. Chem. 277 (10): 8243–7. doi:10.1074/jbc.M109984200. PMID 11756452.
10. Krapivinsky G, Pu W, Wickman K, et al. (May 1998). "pICln binds to a mammalian homolog of a yeast protein involved in regulation of cell morphology". J. Biol. Chem. 273 (18): 10811–4. doi:10.1074/jbc.273.18.10811. PMID 9556550.
11. Friesen WJ, Paushkin S, Wyce A, et al. (Dec 2001). "The methylosome, a 20S complex containing JBP1 and pICln, produces dimethylarginine-modified Sm proteins". Mol. Cell. Biol. 21 (24): 8289–300. doi:10.1128/MCB.21.24.8289-8300.2001. PMC 99994. PMID 11713266.
12. Krzyzanowski A, Gasper R, Adihou H, et al. (Feb 2021). "Biochemical Investigation of the Interaction of pICln, RioK1 and COPR5 with the PRMT5-MEP50 Complex". ChemBioChem. 22 (11): 1908–1914. doi:10.1002/cbic.202100079. PMC 8252068. PMID 33624332.
13. Pollack BP, Kotenko SV, He W, et al. (Oct 1999). "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. doi:10.1074/jbc.274.44.31531. PMID 10531356.
14. Kwak YT, Guo J, Prajapati S, et al. (Apr 2003). "Methylation of SPT5 regulates its interaction with RNA polymerase II and transcriptional elongation properties". Mol. Cell. 11 (4): 1055–66. doi:10.1016/s1097-2765(03)00101-1. PMID 12718890.
15. Guderian G, Peter C, Wiesner J, et al. (Jan 2011). "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. doi:10.1074/jbc.M110.148486. PMC 3023494. PMID 21081503.
16. Mulvaney KM, Blomquis C, Acharya N, et al. (Aug 2020). "Molecular basis for substrate recruitment to the PRMT5 methylosome (preprint)". bioRxiv 10.1101/2020.08.22.256347.
17. McKinney DC, McMillan BJ, Ranaghan MJ, et al. (August 2021). "Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction". Journal of Medicinal Chemistry. 64 (15): 11148–11168. doi:10.1021/acs.jmedchem.1c00507. PMC 9036822. PMID 34342224. S2CID 236884799.
18. Krzyzanowski A, Esser LM, Willaume A, et al. (Nov 2022). "Development of Macrocyclic PRMT5-Adaptor Protein Interaction Inhibitors". J. Med. Chem. 65 (22): 15300–15311. doi:10.1021/acs.jmedchem.2c01273. PMC 9706563. PMID 36378254.
19. Asberry AM, Cai X, Deng X, et al. (October 2022). "Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors". Journal of Medicinal Chemistry. 65 (20): 13793–13812. doi:10.1021/acs.jmedchem.2c01000. PMC 11167723. PMID 36206451. S2CID 252758808.
20. Fu S, Zheng Q, Zhang D, et al. (December 2022). "Medicinal chemistry strategies targeting PRMT5 for cancer therapy". European Journal of Medicinal Chemistry. 244: 114842. doi:10.1016/j.ejmech.2022.114842. PMID 36274274. S2CID 252956172.

Further reading

• Schwärzler A, Kreienkamp HJ, Richter D (2000). "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. doi:10.1074/jbc.275.13.9557. PMID 10734105.
• Rho J, Choi S, Seong YR, et al. (2001). "Prmt5, which forms distinct homo-oligomers, is a member of the protein-arginine methyltransferase family". J. Biol. Chem. 276 (14): 11393–401. doi:10.1074/jbc.M008660200. PMID 11152681.
• Brahms H, Meheus L, de Brabandere V, et al. (2001). "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. doi:10.1017/S135583820101442X. PMC 1370196. PMID 11720283.
• Meister G, Eggert C, Bühler D, et al. (2002). "Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln". Curr. Biol. 11 (24): 1990–4. doi:10.1016/S0960-9822(01)00592-9. hdl:11858/00-001M-0000-0012-F501-7. PMID 11747828. S2CID 14742376.
• Fabbrizio E, El Messaoudi S, Polanowska J, et al. (2003). "Negative regulation of transcription by the type II arginine methyltransferase PRMT5". EMBO Rep. 3 (7): 641–5. doi:10.1093/embo-reports/kvf136. PMC 1084190. PMID 12101096.
• Jiang LQ, Wen SJ, Wang HY, et al. (2003). "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. doi:10.1291/hypres.25.647. PMID 12358155.
• Gevaert K, Goethals M, Martens L, et al. (2004). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nat. Biotechnol. 21 (5): 566–9. doi:10.1038/nbt810. PMID 12665801. S2CID 23783563.
• Pal S, Yun R, Datta A, et al. (2003). "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. doi:10.1128/MCB.23.21.7475-7487.2003. PMC 207647. PMID 14559996.
• Yanagida M, Hayano T, Yamauchi Y, et al. (2004). "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. doi:10.1074/jbc.M305604200. PMID 14583623.
• Jin J, Smith FD, Stark C, et al. (2004). "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. Bibcode:2004CBio...14.1436J. doi:10.1016/j.cub.2004.07.051. PMID 15324660. S2CID 2371325.
• Miranda TB, Khusial P, Cook JR, et al. (2004). "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. doi:10.1016/j.bbrc.2004.08.107. PMID 15369763.
• Pal S, Vishwanath SN, Erdjument-Bromage H, et al. (2004). "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. doi:10.1128/MCB.24.21.9630-9645.2004. PMC 522266. PMID 15485929.