Abstract
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.
Highlights
Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets
Several elegant studies using Prmt[7] knockout mouse models revealed the role of this methyltransferase in maintenance of muscle satellite cell quiescence, muscle oxidative metabolism, and B cell biology[12,13,14]. These studies have greatly expanded our understanding of PRMT7 biology, it remains an understudied member of the PRMT family with poor understanding of its cellular substrates
Proteomics studies have identified an abundance of cellular monomethyl arginine-containing proteins[24,25,26,27], as other PRMT family members may be responsible for this methylation, it is not clear which of these substrates are dependent on PRMT7 as systematic studies of PRMT7 cellular substrates are lacking
Summary
Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. 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. Several elegant studies using Prmt[7] knockout mouse models revealed the role of this methyltransferase in maintenance of muscle satellite cell quiescence, muscle oxidative metabolism, and B cell biology[12,13,14] These studies have greatly expanded our understanding of PRMT7 biology, it remains an understudied member of the PRMT family with poor understanding of its cellular substrates. SGC3027 inhibits the PRMT7driven methylation impacting the thermotolerance and proteostatic stress response in cells
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