The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
PRMT arginine methylation site
Functional site description:
Arginine methylation is an important post-translational modification found in both nuclear and cytoplasmic proteins. The methylation of arginine residues is catalyzed by the protein arginine N-methyltransferase (PRMT) family of enzymes. The methylated arginine residue often appears as a part of two or three RG or RGG repeated sequences. The methylated region acts as a binding site for proteins as well as nucleic acid sequences and they are involved in various physiological processes such as transcription, pre-mRNA splicing, DNA damage signaling, mRNA translation and the regulation of apoptosis.
ELM Description:
RGG/RG motifs are substrate recognition sites for multiple protein arginine methyltransferases (PRMTs). A variant arginine methylation site, GGRGG is a strong substrate for some PRMTs including PRMT1 and is conserved in some proteins, such as Fus and nucleolin, often as part of RGG repeats. GGRGG is conserved in E. coli Tir proteins and in proteins of some other bacterial pathogens. The presence of glycine neighboring arginine is predicted to enhance conformational flexibility and facilitate the access of the arginine to the active site of PRMTs.Other positively charged amino acids, such as lysine and histidine, are not found within motifs, suggesting that arginine confers distinct properties to the motif besides its positive charge.
Pattern: GGRGG
Pattern Probability: 0.0000019
Present in taxon: Eukaryota
o Abstract
The RGG box proteins are a class of RNA-binding proteins (RBPs) involved in various aspects of RNA processing, including splicing, stabilization, transport and translation of mRNAs (Bedford,2005). Methylation of the arginine residue in the RGG motif also acts as an epigenetic regulator of transcription and protein binding. Mutations in proteins containing RGG/RG sites are implicated in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), fragile X syndrome and spinal muscular atrophy (Thandapani,2013). Protein arginine methyltransferases (PRMTs) catalyze the transfer of a methyl group from S-adenosylmethionine (SAM) to the guanidino nitrogen atoms of arginine. This reaction results in the formation of methylarginine and S-adenosylhomocysteine. Arginine can be methylated in three different ways on the guanidino group: monomethylated (MMA), symmetrically dimethylated (sDMA) and asymmetrically dimethylated (aDMA), each of which has potentially different functional consequences. PRMTs fall into three categories according to their catalytic activity; type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) and type II (PRMT5 and PRMT9) enzymes carry out the formation of MMA as an intermediate before the establishment of aDMA or sDMA, respectively. PRMT7 is a type III enzyme that catalyzes only the formation of MMA. Not all PRMTs methylate RGG/RG motifs. These methylated arginine motifs are known as glycine-arginine–rich (GAR) regions and appear as two to three repeats of RGG or RG sequences(Thandapani,2013). The presence of glycine on the C-terminal side of the arginine residue seems to be a strong prerequisite for the recognition by PRMTs (Kim,1997), however a focused peptide array showed that other residues like Leu,Tyr,Phe,Thr and Lys are allowed for PRMT1-dependent methylation in the GGRxG peptide context (18700728). The tumorigenesis-associated PRMT5 has nuclear and cytosolic activities with a preference for an Arginine sandwiched by two neighboring glycines (GRG motif), additional glycines were not necessary (30940768). Motif preferences are not well known for some of the PRMTs.
RGG/RG motif methylation has been reported in viral proteins. The mRNA export factor ICP27 from Human herpes simplex virus 1 has a 15 amino acids long RGG box with three RGG/RG motifs. One or more of these arginine residues can be methylated in vivo primarily in the nucleus (19913501). The late region 4 100K protein from adenovirus type 5 is arginine-methylated by PRMT1 at GRGG motifs in the nucleus (19264777).
A variant of RGG/RG and GRG motifs are GGRGG motifs. They have been identified in many nuclear proteins including heterogeneous nuclear ribonucleoproteins (hnRNPs), fibrillarin, nucleolin and EWS protein and are often found to be asymmetrically dimethylated (Kim,1997; 11850402; 15044439). Methylation affects the nucleocytoplasmic shuttling of EWS protein and hnRNPK. (Belyanskaya,2001; Chang,2011). Studies have shown that nuclear hnRNPs are highly methylated. Though arginine dimethylation of nuclear hnRNPs is evolutionarily conserved from lower eukaryotes to mammals, it is differentially methylated. Multiple hnRNP A/B paralogs and multiple alternatively spliced isoforms of each paralog have different patterns of arginine methylation and hence impart functional diversity upon the hnRNP A/B protein(Friend,2013). A survey for di-methylated nuclear proteins showed that they prefer the symmetrical GGRGG motif with an additional preference for Gly/Phe residues at both borders (Kim,1997).

Given these observations and that GGRGG is a very good substrate for some PRMTs (Kim,1997), this entry is currently exclusive to that sequence. RGG and GRG motifs may be added later.
Functional GGRGG motifs in bacteria have not been described; however, some effector proteins in human pathogens have conserved GGRGG motifs. The Translocated intimin receptor (Tir) from Escherichia coli is a substrate of the Type three secretion system and works as a receptor for intimin after it anchors with two transmembrane domains to the targeted epithelial cell. Tir has a conserved GGRGG motif within the intracellular N-terminal region. Other proteins like the Uncharacterized BAB1_1820 from Brucella abortus and the putative exported protein BB4666 from Bordetella bronchiseptica also have conserved GGRGG motifs.
o 9 selected references:

o 11 GO-Terms:

o No Instance for MOD_PRMT_GGRGG_1
Please cite: The eukaryotic linear motif resource - 2018 update. (PMID:29136216)

ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement