Protein Arginine Methyltransferases: from Unicellular Eukaryotes to Humans

Eukaryotic cells extend their polypeptide diversity beyond the constraints of the encoded amino acids by means of posttranslational modifications.These modifications regulate the stability, localization, activity, and probably other as-yet-uncharacterized protein functions.Methylated derivatives of arginines were identified 40 years ago from acidic lysates of nuclear extracts (69).However, the first genes encoding protein arginine methyltransferases (PRMTs) were identified only a decade ago (29,37,54).Since this important discovery, the study of protein arginine methylation has been a rapidly expanding field, and PRMT-encoding genes have been identified from the sequenced genomes of yeasts, worm, fly, plants, and mammals but not prokaryotes (7,28,60).Here, I will focus on the current knowledge of PRMTs predicted to be expressed in several unicellular eukaryotic species.References and comparisons to the functional roles played by these evolutionarily conserved PRMTs in higher eukaryotes, especially humans, will also be discussed.PRMTs are divided into four major classes depending on the type of methylarginine they generate (Fig. 1A).Type I and II PRMTs both catalyze monomethylation of the guanidinium () nitrogen of specific arginine residues in proteins; yet, they differ on the type of dimethylarginine they generate (Fig. 1A).Type I PRMTs modify proteins by the catalysis of asymmetric N G ,N Gdimethylarginine, whereas type II PRMTs catalyze the formation of symmetric N G ,NЈ G -dimethylarginine.Type III enzymes catalyze only the monomethylation of arginine residues in proteins (64).It remains unclear, however, whether such enzymes are dedicated for the catalysis of -N G -monomethylarginine or if the modified monomethylarginine is an intermediate to additional steps of methylation.A less common form of methylarginine is one in which the delta (␦) nitrogen atom of arginine residues is modified by type IV PRMTs (Fig. 1A).As yet, protein arginine methylation by the type IV PRMTs has been characterized only in Saccharomyces cerevisiae (67) and is less abundant than protein arginine methylation of the guanidinium nitrogen.In humans, nine PRMTs have so far been identified (Fig. 1B): the type I arginine methyltransferases PRMT1, PRMT3, PRMT4, PRMT6, and PRMT8, as well as those of type II, PRMT5, PRMT7, and PRMT9.Although PRMT2 demonstrates a significant degree of similarity to PRMT1, no enzymatic activity has yet been described for human PRMT2 (83).As can be seen in Fig. 1B, the primary structure of each PRMT shares a conserved methyltransferase domain that includes subdomains for binding to the methyl donor, S-adenosyl-L-methionine (SAM) and substrate proteins.