Enzyme for Delta Antigen Methylation

Arginine methylation involves the addition of one or two methyl groups to the guanidine nitrogen atoms of arginine (Gary and Clarke 1998; McBride and

Silver 2001). Arginine maybe dimethylated asymmetrically or symmetrically. At least three types of protein arginine methyltransferase (PRMT) activities have been reported (Lee et al. 1977). PRMT1 (Tang et al. 2000a), PRMT3 (Tang et al. 1998), PRMT6 (Frankel et al. 2002), and coactivator-associated arginine methyltransferase 1 (CARM1, also known as PRMT4) (Chen et al. 1999a) are type I enzymes. PRMT5 is so far the only known type II enzyme (Branscombe et al. 2001). Another class of PRMTs, including PRMT7, only catalyzes the formation of monomethylarginines (Miranda et al. 2004). No clear consensus sequences/motifs are known for CARM1 substrates or for the newly identified PRMT6 and PRMT7.

In vitro analysis demonstrated that S-HDAg was methylated by PRMT1, but not other type I protein PRMTs including PRMT3 and CARM1. PRMT1 is the predominant type I protein arginine methyltransferase in mammalian cells (Tang et al. 2000a). It is localized in the nucleus and catalyzes methylation on arginine residues in RGG, RXR or GAR motifs of several proteins (Boisvert et al. 2003; Liu and Dreyfuss 1995; Wada et al. 2002). The substrates of PRMT1 involve several proteins, including many RNA-binding proteins, transporting proteins, transcription factors, and nuclear matrix proteins (Abramovich et al. 1997; Mowen et al. 2001; Nichols et al. 2000; Smith et al. 1999; Smith et al. 2004; Tang et al. 2000b).

It is noteworthy that PRMT5 (type II) also preferentially catalyzes arginine methylation located in RG-rich clusters (Boisvert et al. 2003), and cellular proteins, such as DRB-sensitive inducing factor (DSIF), p160 or Spt5, were identified to be arginine methylated by PRMT1 as well as PRMT5 (Kwak et al. 2003). PRMT6, which is also a type I PRMT, catalyzed methylation on arginine-rich motif (ARM) of HIV-1 Tat protein (Boulanger et al. 2005). Notably, the RNA binding domain of HDAg contains two ARMs (Lee et al. 1993). Hence, the possible involvement of PRMTs in addition to PRMT1 (i.e. PRMT5, PRMT6) in arginine methylation of S-HDAg still requires further exploration.

Moreover, methylation of lysine residue(s) also occurs in HDAg, as Li et al. mentioned that antibodies detecting methylated lysine residues could recognize cellular HDAg. This result indicates the possible involvement of lysine methyl transferases such as the SET domain-containing methyltransferase family (Nishioka et al. 2002; Strahl et al. 2002), and suggests the possibility that, similar to histones, S-HDAg methylation might be catalyzed by two families of proteins—one that methylates arginine residues, the other lysine residues.

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