Poster Presentation 23rd Annual Lorne Proteomics Symposium 2018

Investigating the substrate recognition motifs of Hmt1 and PRMT1 (#74)

Ryan J Separovich 1 , Joshua J Hamey 1 , Marc R Wilkins 1
  1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia

Arginine methylation is a widespread and functionally-important post-translational modification (PTM) found on over 700 eukaryotic proteins. Methylation of arginine residues has been shown to modulate protein-protein interactions involved in many cellular processes, including transcriptional regulation, RNA processing, signal transduction, and DNA repair. The majority of arginine methylation in the Saccharomyces cerevisiae proteome is catalysed by the protein arginine methyltransferase (PRMT), Hmt1, and its mammalian orthologue PRMT1 similarly accounts for most arginine methylation in the human cell. For the past thirty years, the arginine-glycine-glycine (RGG) motif has been widely recognised as a canonical substrate recognition sequence for both Hmt1 and PRMT1. Despite the functional importance and diverse substrates of these enzymes, their complete substrate recognition motifs have, until now, remained undefined. To this end, we employed a novel motif analysis technique to quantitatively and comprehensively investigate the effects of different amino acid residues in nearby positions on Hmt1- and PRMT1-mediated methylation, and thereby elucidate their full substrate recognition sequences. Our novel motifs revealed that, while the ‘RGG’ sequence is still central to PRMT substrate specificity, this model is oversimplified and does not adequately portray the complex intricacies of this process. We have, for the first time, directly confirmed the importance of aromatic residues in the +3 position for Hmt1 activity. Our results also highlighted Hmt1’s intolerance for the negatively-charged, acidic amino acids in the upstream positions, an observation strengthening evidence for methylation-phosphorylation crosstalk. Compared with its yeast counterpart, PRMT1 exhibited slightly broader specificity, likely indicative of its more numerous cellular substrates. The refined motifs determined through this study provide unique insights into the molecular mechanisms of substrate recognition employed by these enzymes, and may therefore inform the development of novel therapeutic agents targeting PRMT1, or facilitate the prediction of additional Hmt1 and PRMT1 substrates.