PRMT5
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPRMT5, HRMT1L5, IBP72, JBP1, SKB1, SKB1Hs, Protein arginine methyltransferase 5, HSL7
External IDsOMIM: 604045 MGI: 1351645 HomoloGene: 4454 GeneCards: PRMT5
EC number2.1.1.321
Orthologs
SpeciesHumanMouse
Entrez

10419

27374

Ensembl

ENSG00000100462

ENSMUSG00000023110

UniProt

O14744

Q8CIG8

RefSeq (mRNA)

NM_013768
NM_001313906
NM_001313907

RefSeq (protein)

NP_001300835
NP_001300836
NP_038796

Location (UCSC)Chr 14: 22.92 – 22.93 MbChr 14: 54.74 – 54.75 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 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:

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. 1 2 3 GRCh38: Ensembl release 89: ENSG00000100462 - Ensembl, May 2017
  2. 1 2 3 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, Pimental RA, Kansra S, Gadiraju R, Marcus S (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, Zylicz JJ, Hackett, JA, Cougot, D, Bao, S, Lee, C, Dietmann, S, Allen, GE, Sngupta, R, Surani MA (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. 1 2 Friesen WJ, Wyce A, Paushkin S, Abel L, Rappsilber J, Mann M, Dreyfuss G (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, Krapivinsky L, Clapham DE (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. 1 2 Friesen WJ, Paushkin S, Wyce A, Massenet S, Pesiridis GS, Van Duyne G, Rappsilber J, Mann M, Dreyfuss G (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. 1 2 3 4 Krzyzanowski A, Gasper R, Adihou H, 't Hart P, Waldmann H (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, Izotova LS, Barnoski BL, Pestka S (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, Park KJ, Surabhi RM, Miller B, Gehrig P, Gaynor RB (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, Sickmann A, Schulze-Osthoff K, Fischer U, Grimmler M (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, 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)". bioRxiv 10.1101/2020.08.22.256347.
  17. McKinney DC, McMillan BJ, Ranaghan MJ, Moroco JA, Brousseau M, Mullin-Bernstein Z, 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, Prudent R, Peter C, 't Hart P, Waldmann H (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, Santiago U, Liu S, Sims HS, 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. PMID 36206451. S2CID 252758808.
  20. Fu S, Zheng Q, Zhang D, Lin C, Ouyang L, Zhang J, Chen L (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

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