Protein arginine methyltransferase 5

Last updated
PRMT5
6ckc2.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PRMT5 , HRMT1L5, IBP72, JBP1, SKB1, SKB1Hs, Protein arginine methyltransferase 5, HSL7
External IDs OMIM: 604045 MGI: 1351645 HomoloGene: 4454 GeneCards: PRMT5
EC number 2.1.1.321
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_013768
NM_001313906
NM_001313907

RefSeq (protein)

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

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]

Related Research Articles

<span class="mw-page-title-main">Histone methyltransferase</span> Histone-modifying enzymes

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

<span class="mw-page-title-main">Adapter molecule crk</span> Protein-coding gene in the species Homo sapiens

Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.

<span class="mw-page-title-main">GRB10</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.

<span class="mw-page-title-main">PRMT1</span> Protein-coding gene in the species Homo sapiens

Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the PRMT1 gene. The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.

<span class="mw-page-title-main">CDC6</span> Protein-coding gene in the species Homo sapiens

Cell division control protein 6 homolog is a protein that in humans is encoded by the CDC6 gene.

<span class="mw-page-title-main">RBBP7</span> Protein-coding gene in the species Homo sapiens

Histone-binding protein RBBP7 is a protein that in humans is encoded by the RBBP7 gene.

<span class="mw-page-title-main">GNAO1</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein G(o) subunit alpha is a protein that in humans is encoded by the GNAO1 gene.

<span class="mw-page-title-main">PRKAB1</span> Protein-coding gene in the species Homo sapiens

5'-AMP-activated protein kinase subunit beta-1 is an enzyme that in humans is encoded by the PRKAB1 gene.

<span class="mw-page-title-main">Protein inhibitor of activated STAT2</span> Protein-coding gene in the species Homo sapiens

E3 SUMO-protein ligase PIAS2 is an enzyme that in humans is encoded by the PIAS2 gene.

<span class="mw-page-title-main">APBA1</span> Protein-coding gene in the species Homo sapiens

Amyloid beta A4 precursor protein-binding family A member 1 is a protein that in humans is encoded by the APBA1 gene.

<span class="mw-page-title-main">SNRPD3</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D3 is a protein that in humans is encoded by the SNRPD3 gene.

<span class="mw-page-title-main">DMAP1</span> Protein-coding gene in the species Homo sapiens

DNA methyltransferase 1-associated protein 1 is an enzyme that in humans is encoded by the DMAP1 gene.

<span class="mw-page-title-main">CLNS1A</span> Protein-coding gene in humans

Methylosome subunit pICln is a protein that in humans is encoded by the CLNS1A gene.

<span class="mw-page-title-main">SNX9</span> Protein-coding gene in the species Homo sapiens

Sorting nexin-9 is a protein that in humans is encoded by the SNX9 gene.

<span class="mw-page-title-main">RANBP1</span> Protein-coding gene in the species Homo sapiens

Ran-specific binding protein 1 is an enzyme that in humans is encoded by the RANBP1 gene.

<span class="mw-page-title-main">WD repeat-containing protein 77</span> Protein-coding gene in the species Homo sapiens

Methylosome protein 50 is a protein that in humans is encoded by the WDR77 gene.

<span class="mw-page-title-main">GRB14</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 14 is a protein that in humans is encoded by the GRB14 gene.

<span class="mw-page-title-main">SORBS3</span> Protein-coding gene in the species Homo sapiens

Vinexin is a protein that in humans is encoded by the SORBS3 gene.

<span class="mw-page-title-main">PRMT2</span> Protein-coding gene in the species Homo sapiens

Protein arginine N-methyltransferase 2 is an enzyme that in humans is encoded by the PRMT2 gene.

<span class="mw-page-title-main">RIOK1</span> Protein-coding gene in humans

Serine/threonine-protein kinase RIO1 is an enzyme that in humans is encoded by the RIOK1 gene.

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, 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. 1 2 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. 1 2 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. 1 2 3 4 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. 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