Investigating Arginine Methylation of PGC-1alpha, a Master Metabolic Regulator

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha, UniProt Q9UBK2), acts as a transcriptional coactivator capable of regulating metabolic pathways. It has regulatory functions in lipid metabolism, mitochondrial biogenesis, and remodeling of muscle tissue. Thus, PGC-1alpha has been implicated in diseases such as type 2 diabetes and obesity, cancer, and neurodegenerative diseases such as Parkinson’s disease. We set out to investigate the control points of PGC-1alpha by focusing on one posttranslational modification (PTM) called arginine methylation. Arginine methylation increases the structural diversity of proteins and often plays a role in protein-protein interactions. Studies show that PGC-1alpha contains arginine residues that are methylated by protein arginine methyltransferase 1 (PRMT1). Since there are other members of the PRMT family, we hypothesize that the methylation of PGC-1alpha is critical for its role as a master regulator by PRMT7. PRMT7 was used because it is a unique member of the methyltransferase family. Not only is it larger than the rest of the family members, but it is also the only known member of the PRMT family capable of producing only omega-monomethylated arginine (omega-MMA) residues. In addition, it prefers to methylate arginine residues found in RXR motifs (where R represents arginine, X represents any amino acid) surrounded by basic amino acids. PGC-1alpha contains four RXR, three RXRXR, and one RXRXRXR arginine-rich regions and like PRMT7 functions at temperatures outside of 37˚C. In vitro methylation reactions using purified recombinant mammalian PRMT7 and PGC-1alpha were performed. Methylation reactions by PRMT7 show that PGC-1alpha arginine residues R568 and R570 become monomethylated and are temperature-dependent. These results elucidate novel posttranslational modifications that may act as control points for the regulation of PGC-1alpha. We next aim to continue this work by focusing on the significance of monomethylating PGC-1alpha at arginine residues R568 and R570