Nomega-arginine dimethylation modulates the interaction between a Gly/Arg-rich peptide from human nucleolin and nucleic acids

Raman, Baktisaran; Guarnaccia, Corrado; Nadassy, Katalin; Zakhariev, S.; Pintar, Alessandro; Zanuttin, Francesco; Frigyes, Dávid; Acatrinei, C.; Vindigni, Alessandro; Pongor, G.; Pongor, Sándor

doi:10.1093/nar/29.16.3377

Cited by 54 publications

(50 citation statements)

References 23 publications

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“…Thus, methylation of the RGG/RG motif may cause a reorganization of the disordered regions in the AUF1 p45 C terminus, which, in turn, would facilitate disorder to order transitions in the restructuring of the WNV 3 ′ SL. While this scenario is speculative, it is in agreement with earlier data of Raman et al (2001) showing that the dimethylation of a protein's RGG motifs may alter the structure of the RNA to which these RGG motifs bind. Our findings also go well with studies indicating that the AUF1 isoforms may differently alter the local structures of model ARE substrates (Wilson et al 2001;Zucconi et al 2010) and that phosphorylation of AUF1 p40 may affect the conformation of a bound RNA (Wilson et al 2003).…”

Section: Discussionsupporting

confidence: 89%

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Friedrich

Schmidt

Schierhorn

et al. 2016

RNA

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A prerequisite for the intracellular replication process of the Flavivirus West Nile virus (WNV) is the cyclization of the viral RNA genome, which enables the viral replicase to initiate RNA synthesis. Our earlier studies indicated that the p45 isoform of the cellular AU-rich element binding protein 1 (AUF1) has an RNA chaperone activity, which supports RNA cyclization and viral RNA synthesis by destabilizing a stem structure at the WNV RNA's 3 ′ -end. Here we show that in mammalian cells, AUF1 p45 is consistently modified by arginine methylation of its C terminus. By a combination of different experimental approaches, we can demonstrate that the methyltransferase PRMT1 is necessary and sufficient for AUF1 p45 methylation and that PRMT1 is required for efficient WNV replication. Interestingly, in comparison to the nonmethylated AUF1 p45, the methylated AUF1 p45 aDMA exhibits a significantly increased affinity to the WNV RNA termini. Further data also revealed that the RNA chaperone activity of AUF1 p45 aDMA is improved and the methylated protein stimulates viral RNA synthesis considerably more efficiently than the nonmethylated AUF1 p45. In addition to its destabilizing RNA chaperone activity, we identified an RNA annealing activity of AUF1 p45, which is not affected by methylation. Arginine methylation of AUF1 p45 thus represents a specific determinant of its RNA chaperone activity while functioning as a WNV host factor. Our data suggest that the methylation modifies the conformation of AUF1 p45 and in this way affects its RNA binding and restructuring activities.

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Section: Discussionsupporting

confidence: 89%

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Friedrich

Schmidt

Schierhorn

et al. 2016

RNA

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“…Asymmetric dimethylation of the guanidinium group of arginine has several physicochemical effects: Increased hydrophobicity, a decrease of the hydrogen bonding ability, and a slightly lower pK value [29]. An additional effect of N G -methylation is loss of planarity of the nitrogen atoms in the guanidinium group, probably due to steric hindrance.…”

Section: Resultsmentioning

confidence: 99%

Fragmentation pathways of N^G-methylated and unmodified arginine residues in peptides studied by ESI-MS/MS and MALDI-MS

Gehrig

Hunziker

Zahariev

et al. 2004

J. Am. Soc. Mass Spectrom.

103

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Protein methylation at arginine residues is a prevalent posttranslational modification in eukaryotic cells that has been implicated in processes from RNA-binding and transporting to protein sorting and transcription activation. Three main forms of methylarginine have been identified: N G -monomethylarginine (MMA), asymmetric N G ,N G -dimethylarginine (aDMA), and symmetric N G ,NЈ G -dimethylarginine (sDMA). To investigate gas-phase fragmentations and characteristic ions arising from methylated and unmodified arginine residues in detail, we subjected peptides containing these residues to electrospray triple-quadrupole tandem mass spectrometry. A variety of low mass ions including (methylated) ammonium, carbodiimidium, and guanidinium ions were observed. Fragment ions resulting from the loss of the corresponding neutral fragments (amines, carbodiimide, and guanidine) from intact molecular ions as well as from N-and C-terminal fragment ions were also identified. Furthermore, the peptides containing either methylated or unmodified arginines gave rise to abundant fragment ions at m/z 70, 112, and 115, for which cyclic ion structures are proposed. Electrospray ionization tandem mass spectra revealed that dimethylammonium (m/z 46) is a specific marker ion for aDMA. A precursor ion scanning method utilizing this fragment ion was developed, which allowed sensitive and specific detection of aDMA-containing peptides even in the presence of a five-fold excess of phosphorylase B digest. Interestingly, regular matrix-assisted laser desorption/ionization mass spectra recorded from aDMA-or sDMA-containing peptides showed metastable fragment ions resulting from cleavages of the arginine side chains. The neutral losses of mono-and dimethylamines permit the differentiation between aDMA and sDMA. (J Am Soc Mass Spectrom 2004, 15, 142Ϫ149)

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“…Valentini et al as well as Raman et al reported that methylation does not specifically affect RNA binding. 53,54 On the other hand, Rajpurohit et al reported that binding of recombinant hnRNP A1 protein to singlestranded nucleic acid is slightly reduced following arginine methylation. 55 The GAR motifs by themselves do not appear to mediate nonspecific binding to nucleic acids and in some cases may mediate sequence-specific RNA binding as demonstrated for nucleolin, hnRNP A1, hnRNP U and ICP27.…”

Section: Discussionmentioning

confidence: 99%

The GAR Motif of 53BP1 is Arginine Methylated by PRMT1 and is Necessary for 53BP1 DNA Binding Activity

Boisvert¹,

Rhie²,

Richard³

et al. 2005

Cell Cycle

124

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The p53-binding protein 1 (53BP1) is rapidly recruited to sites of DNA double-strand breaks and forms characteristics nuclear foci, demonstrating its role in the early events of detection, signaling and repair of damaged DNA. 53BP1 contains a glycine arginine rich (GAR) motif of unknown function within its kinetochore-binding domain. Herein, we show that the GAR motif of 53BP1 is arginine methylated by protein arginine methyltransferase 1 (PRMT1), the same methyltransferase that methylates MRE11. 53BP1 contains asymmetric dimethylarginines (aDMA) within cells, as detected with methylargininespecific antibodies. Amino acid substitution of the arginines within the GAR motif of 53BP1 abrogated binding to single and double-stranded DNA, demonstrating that the GAR motif is required for DNA binding activity of 53BP1. Fibroblast cells treated with methylase inhibitors failed to relocalize 53BP1 to sites of DNA damage and formed few γ-H2AX foci, consistent with our previous data that MRE11 fails to relocalize to DNA damage sites in cells treated with methylase inhibitors. Our findings identify the GAR motif as a region required for 53BP1 DNA binding activity and as the site of methylation by PRMT1.

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Nomega-arginine dimethylation modulates the interaction between a Gly/Arg-rich peptide from human nucleolin and nucleic acids

Cited by 54 publications

References 23 publications

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Fragmentation pathways of N^G-methylated and unmodified arginine residues in peptides studied by ESI-MS/MS and MALDI-MS

The GAR Motif of 53BP1 is Arginine Methylated by PRMT1 and is Necessary for 53BP1 DNA Binding Activity

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Nomega-arginine dimethylation modulates the interaction between a Gly/Arg-rich peptide from human nucleolin and nucleic acids

Cited by 54 publications

References 23 publications

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Fragmentation pathways of NG-methylated and unmodified arginine residues in peptides studied by ESI-MS/MS and MALDI-MS

The GAR Motif of 53BP1 is Arginine Methylated by PRMT1 and is Necessary for 53BP1 DNA Binding Activity

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Fragmentation pathways of N^G-methylated and unmodified arginine residues in peptides studied by ESI-MS/MS and MALDI-MS