Dysregulated protein arginine methylation is linked to cancer and a variety of other human diseases. Protein arginine methylation is catalyzed by the Protein Arginine Methyltransferase (PRMT) enzyme family. PRMT1 is the predominant PRMT isoform in mammalian cells and acts in pathways regulating transcription, DNA repair, apoptosis, and cell proliferation. PRMT1 dimer formation is required for methyltransferase activity and is mediated by interactions between a structure called the dimerization arm on one monomer, and a surface on a Rossman Fold of the other monomer. Given the link between PRMT1 dysregulation and disease and the link between PRMT1 dimerization and activity, we searched the Catalogue of Somatic Mutations in Cancer (COSMIC) database to identify potentially inactivating mutations occurring in the PRMT1 dimerization arm. We identified three mutations which correspond to W215L, Y220N, and M224V substitutions in human PRMT1V2. Using a combination of site-directed mutagenesis, analytical ultracentrifugation, native PAGE, and activity assays, we found that these conservative substitutions surprisingly disrupt oligomer formation and substantially impair both AdoMet binding and methyltransferase activity. Accelerated molecular dynamics trajectories suggest that these substitutions introduce novel interactions within the dimerization arm that lock it in a conformation not conducive to dimer formation.

Cancer-associated mutations disrupt oligomerization and activity in PRMT1

ACS Spring 2022

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