Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.
Animals
Arginine
/ metabolism
Gene Knockdown Techniques
HCT116 Cells
HSP70 Heat-Shock Proteins
/ metabolism
Humans
Methylation
/ drug effects
Protein Processing, Post-Translational
/ drug effects
Protein-Arginine N-Methyltransferases
/ antagonists & inhibitors
Recombinant Proteins
/ genetics
Sf9 Cells
Stress, Physiological
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 05 2020
14 05 2020
Historique:
received:
26
03
2019
accepted:
20
04
2020
entrez:
16
5
2020
pubmed:
16
5
2020
medline:
1
9
2020
Statut:
epublish
Résumé
Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.
Identifiants
pubmed: 32409666
doi: 10.1038/s41467-020-16271-z
pii: 10.1038/s41467-020-16271-z
pmc: PMC7224190
doi:
Substances chimiques
HSP70 Heat-Shock Proteins
0
Recombinant Proteins
0
Arginine
94ZLA3W45F
PRMT7 protein, human
EC 2.1.1.319
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2396Subventions
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Organisme : CIHR
Pays : Canada
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : Wellcome Trust
ID : 106169/ZZ14/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
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