<br/>Increased attention has been placed on dysregulated protein arginine methylation due to its link to cancer and an assortment of other diseases. The Protein Arginine Methyltransferase (PRMT) enzyme family, for which PRMT1 is the predominant PRMT isoform in mammalian cells, catalyzes protein arginine methylation. Not only does PRMT1 acts as a pathway for DNA repair, transcription, apoptosis, and cell proliferation, its activity and dimerization is also linked to dysregulation and disease. For methyltransferase activity to be promoted a PRMT1 dimer must be successfully formed between the dimerization arm of one monomer and a surface on a Rossman fold of the other monomer. As a result, the Catalogue of Somatic Mutations in Cancer (COSMIC) database was searched to identify potentially inactivating mutations occurring in the PRMT1 dimerization arm. From this search, three mutations which correspond to W215L, Y220N, and M224V substitutions in human PRMT1V2 (W197L, Y202N, M206V in rat PRMT1V1) were identified and experimentally along with computationally studied. Employment of work site-directed mutagenesis, analytical ultracentrifugation, native PAGE, and activity assays, found substitutions impaired S-adenosyl-L-methionine (AdoMet) binding, methyltransferase activity, and disrupted oligomer formation. Theoretical investigations employing accelerated molecular dynamics simulations (aMD) also supported experimental findings and suggested mutated residues lock the dimerization arm of PRMT1 in an unfavorable conformation not conducive to dimer formation.

Cancer-associated mutations disrupt oligomerization and activity in Protein Arginine Methyltransferase 1

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