What can protein methylation tell us about histones, ribosomes, translation factors and the biology of cancer and aging?

Abstract

The chemical diversity of proteins is enhanced by posttranslational methylation of most of the 20 major ribosomally‐incorporated amino acids. The most abundant of these modifications occur at the side chains of lysine and arginine residues, although methylation is also known for histidine, glutamine, asparagine, glutamate, cysteine, and methionine residues, as well as for the alpha‐amino groups of several N‐terminal residues and the alpha‐carboxyl groups of leucine and isoprenylcysteine C‐terminal residues. Methylation reactions also can tag age‐damaged D‐aspartyl and L‐isoaspartyl residues for repair reactions.Protein arginine methylation in mammalian cells is largely catalyzed by the nine members of the PRMT family. We have focused our work on the PRMT5 and PRMT9 species that catalyze symmetric dimethylarginine formation, as well as the PRMT7 species that only catalyzes monomethylarginine formation. PRMT9 appears to be specific for the modification of the SF3B2 splicing factor, whereas PRMT5 and PRMT7 appear to have many physiological substrates, including histones. The latter methylation reactions represent a crucial part of the histone code, and recognition of these methylated residues by protein interaction domains modulates transcription. We have recently explored crosstalk between PRMT5 and PRMT7 in the modification of histone H4. In in vitro experiments using a peptide corresponding to the N‐terminal 21 amino acid residues of histone H4, we showed that the activity of the PRMT5 enzyme at the arginine‐3 residue is greatly enhanced by PRMT7‐dependent methylation of arginine‐17 and/or arginine‐19. These experiments provide evidence that PRMTs can cooperate with each other to affect the final degree of protein modification and epigenetic control. Surprisingly, PRMT7 has very little activity in vitro at 37 °C; it is most active between 10 and 20 °C. This result suggests that PRMT7 may respond to cold stress in the organism.Methylation reactions, including modification at arginine residues, can occur predominately on proteins of the translational apparatus. In the yeast Saccharomyces cerevisiae, some 51 of the approximately 70 methyltransferases modify rRNA (13 enzymes), mRNA (2 enzymes), tRNA (16 enzymes), translation factors (10 enzymes), and ribosomal proteins (10 enzymes). Of particular interest, we have shown that the Sfm1, Hpm1, Rkm3, and Rkm4 enzymes modify arginine, histidine, and lysine residues buried deep within the ribosome; these modified residues may function in protein–RNA interactions rather than protein–protein interactions.Support or Funding InformationThis work is funded by the National Science Foundation Grant MCB‐1714569.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.