The presence of (di-)methylated arginines in proteins and an enzyme responsible
for this process were discovered 50 years ago [1, 2]. A decade later it was found that
the majority of proteins with methylated arginines are nuclear proteins that contain
asymmetrically dimethylated arginine (aDMA) sidechains [3]. Subsequently, it
became clear that not one enzyme but a distinct family of enzymes was responsible
for this post-translational modification [4–8]. The seminal study of Herschman and
co-workers published in 1996 [9] clearly identified and characterized the first
member of the family, PRMT1. In the following decade, new PRMT family members were identified on a near yearly basis resulting in the now known total of nine
PRMTs [10–18].
Whether or not arginine methylation is a dynamic process remains to be proven
unambiguously. Protein arginine deiminases (PADs) are known to hydrolyse the
guanidine moiety of arginine side chains in proteins into citrulline. However, PADs
are not able to convert dimethylated arginines to citrulline [19]. In addition, while
in vivo data suggested the possibility that PADs can convert monomethylated
arginines to citrulline, in vitro studies have not been able to reproduce this activity
[19]. In addition, citrulline can only be converted back into arginine after proteolysis,
but not in the context of an intact protein. Given that it is unlikely that PADs are the
active player in removing methyl groups from methylated arginines, much effort has
been spent at trying to identify a true arginine demethylase. In 2007, the lysine
demethylating enzyme JMJD6 was reported to also demethylate arginines in histones making it the first example of an arginine demethylase [20]. These findings
O
O
S
H 3 C
NH 3
O
N
N
N
N
N
N
N
N
H
H
H
H
H
O
O
Glu 153
O
O
Glu 144
SAM
O
O
Glu 100
HO
HO
H
H
N
O
HN
O
H
O
O
Val 128
Glu 129
Arg 54
H
H
N
N
NH
H
H
N
H
O
H
N
Peptide
Peptide
N
N
N
H
H
H
H
CH 3
N
H
O
H
N
N
N
N
H
H
H
CH 3
CH 3
N
H
O
H
N
N
N
N
H
H
CH 3
H
CH 3
N
H
O
H
N
Type I, II, III
MMA
T y p e I
T y p e II
SAH
sDMA
aDMA
Fig. 1 Schematic overview of the PRMT-binding site (residue numbering PRMT1) showing the
hydrogen bonding interactions of the double E-loop (residues Glu144 and Glu153) with the
guanidine moiety of the arginine sidechain. Cofactor S-adenosyl-L-methionine (SAM) is depicted
in blue and the protein arginine sidechain in red. First monomethylarginine (MMA) is formed
releasing S-adenosyl-L-homocysteine (SAH). MMA is directly converted to asymmetrically
dimethylated arginine (aDMA) by type I PRMTs and to symmetrically dimethylated arginine
(sDMA) by type II PRMTs
162
M. J. van Haren and N. I. Martin
for this process were discovered 50 years ago [1, 2]. A decade later it was found that
the majority of proteins with methylated arginines are nuclear proteins that contain
asymmetrically dimethylated arginine (aDMA) sidechains [3]. Subsequently, it
became clear that not one enzyme but a distinct family of enzymes was responsible
for this post-translational modification [4–8]. The seminal study of Herschman and
co-workers published in 1996 [9] clearly identified and characterized the first
member of the family, PRMT1. In the following decade, new PRMT family members were identified on a near yearly basis resulting in the now known total of nine
PRMTs [10–18].
Whether or not arginine methylation is a dynamic process remains to be proven
unambiguously. Protein arginine deiminases (PADs) are known to hydrolyse the
guanidine moiety of arginine side chains in proteins into citrulline. However, PADs
are not able to convert dimethylated arginines to citrulline [19]. In addition, while
in vivo data suggested the possibility that PADs can convert monomethylated
arginines to citrulline, in vitro studies have not been able to reproduce this activity
[19]. In addition, citrulline can only be converted back into arginine after proteolysis,
but not in the context of an intact protein. Given that it is unlikely that PADs are the
active player in removing methyl groups from methylated arginines, much effort has
been spent at trying to identify a true arginine demethylase. In 2007, the lysine
demethylating enzyme JMJD6 was reported to also demethylate arginines in histones making it the first example of an arginine demethylase [20]. These findings
O
O
S
H 3 C
NH 3
O
N
N
N
N
N
N
N
N
H
H
H
H
H
O
O
Glu 153
O
O
Glu 144
SAM
O
O
Glu 100
HO
HO
H
H
N
O
HN
O
H
O
O
Val 128
Glu 129
Arg 54
H
H
N
N
NH
H
H
N
H
O
H
N
Peptide
Peptide
N
N
N
H
H
H
H
CH 3
N
H
O
H
N
N
N
N
H
H
H
CH 3
CH 3
N
H
O
H
N
N
N
N
H
H
CH 3
H
CH 3
N
H
O
H
N
Type I, II, III
MMA
T y p e I
T y p e II
SAH
sDMA
aDMA
Fig. 1 Schematic overview of the PRMT-binding site (residue numbering PRMT1) showing the
hydrogen bonding interactions of the double E-loop (residues Glu144 and Glu153) with the
guanidine moiety of the arginine sidechain. Cofactor S-adenosyl-L-methionine (SAM) is depicted
in blue and the protein arginine sidechain in red. First monomethylarginine (MMA) is formed
releasing S-adenosyl-L-homocysteine (SAH). MMA is directly converted to asymmetrically
dimethylated arginine (aDMA) by type I PRMTs and to symmetrically dimethylated arginine
(sDMA) by type II PRMTs
162
M. J. van Haren and N. I. Martin