A Remodeled Protein Arginine Methyltransferase 1 (PRMT1) Generates Symmetric Dimethylarginine

Gui, Shanying; Gathiaka, Symon; Li, Jun; Qu, Jun; Acevedo, Orlando; Hevel, Joan M.

doi:10.1074/jbc.m113.535278

Cited by 26 publications

(37 citation statements)

References 39 publications

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“…Recent publications have used kinetic and mass spectrometry analysis to model the reaction mechanism of PRMT5 and mutated PRMT1 in the generation of mono-and symmetric dimethylarginine (43,44,47). We independently confirmed this distributive model of progression to dimethylation through our demonstration that a synthesized monomethylated histone peptide has a 15-fold higher K m than its equivalent unmethylated peptide.…”

Section: Prmt5-mep50 Structural and Enzymatic Conservation-supporting

confidence: 70%

“…The R3me1 peptide was ϳ20-fold less efficiently methylated, with the majority of this effect embedded in the K m , consistent with poor substrate binding. This result is reminiscent of the previously implicated distributive mechanism of catalysis to the dimethyl state (43,44). Additionally, we tested H2A and H4 mono-and dimethylation over time using specific antibodies.…”

Section: Volume 290 • Number 15 • April 10 2015mentioning

confidence: 99%

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Histone H2A and H4 N-terminal Tails Are Positioned by the MEP50 WD Repeat Protein for Efficient Methylation by the PRMT5 Arginine Methyltransferase

Burgos

Wilczek

Onikubo

et al. 2015

Journal of Biological Chemistry

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Background: PRMT5-MEP50 is an arginine methyltransferase with significant roles in development and cancer. Results: MEP50 binds to the histone fold domain and is essential for the efficient use of SAM by PRMT5. Conclusion: MEP50 is essential for methylation of histones H4 and H2A by PRMT5. Significance: The mechanism of histone methylation by PRMT5-MEP50 provides novel insight into methyltransferase mechanisms and therapeutic development.

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Section: Prmt5-mep50 Structural and Enzymatic Conservation-supporting

confidence: 70%

Section: Volume 290 • Number 15 • April 10 2015mentioning

confidence: 99%

Histone H2A and H4 N-terminal Tails Are Positioned by the MEP50 WD Repeat Protein for Efficient Methylation by the PRMT5 Arginine Methyltransferase

Burgos

Wilczek

Onikubo

et al. 2015

Journal of Biological Chemistry

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“…Many groups have demonstrated that active site steric interactions surrounding the substrate arginine residue contribute to enzyme product specificity. For example, changes to one or two residues within the PRMT1 active site have been shown to either alter the distribution of MMA and aDMA products or shift the enzymatic regioselectivity from aDMA to sDMA . This regioselective shift from one or two amino acid changes was also observed in PRMT7 from Trypanosoma brucei , in which an E181D variant expanded this enzyme's product formation to include aDMA, and a E181D/ Q329A double variant formed sDMA .…”

Section: Introductionmentioning

confidence: 84%

Kinetic Analysis of PRMT1 Reveals Multifactorial Processivity and a Sequential Ordered Mechanism

Brown

Koopmans

Strien³

et al. 2017

ChemBioChem

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Arginine methylation is a prevalent post‐translational modification in eukaryotic cells. Two significant debates exist within the field: do these enzymes dimethylate their substrates in a processive or distributive manner, and do these enzymes operate using a random or sequential method of bisubstrate binding? We revealed that human protein arginine N‐methyltransferase 1 (PRMT1) enzyme kinetics are dependent on substrate sequence. Further, peptides containing an Nη‐hydroxyarginine generally demonstrated substrate inhibition and had improved KM values, which evoked a possible role in inhibitor design. We also revealed that the perceived degree of enzyme processivity is a function of both cofactor and enzyme concentration, suggesting that previous conclusions about PRMT sequential methyl transfer mechanisms require reassessment. Finally, we demonstrated a sequential ordered Bi–Bi kinetic mechanism for PRMT1, based on steady‐state kinetic analysis. Together, our data indicate a PRMT1 mechanism of action and processivity that might also extend to other functionally and structurally conserved PRMTs.

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“…Indeed, recent quantum mechanics calculations comparing PRMT1-and PRMT3-catalyzed methylation reactions with protonated or deprotonated substrate arginine showed more favorable free energies of activation for methyl transfers when the arginine residue was neutral. [30,31] Figure 3. Electrostatic potential surrounding Nh-substituted arginine fragments.…”

Section: Nh-substituted Peptides As Type I Prmt Inhibitorsmentioning

confidence: 97%

Protein Arginine N‐Methyltransferase Substrate Preferences for Different Nη‐Substituted Arginyl Peptides

et al. 2014

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Protein arginine N-methyltransferases (PRMTs) catalyze methyl-group transfer from S-adenosyl-L-methionine onto arginine residues in proteins. In this study, modifications were introduced at the guanidine moiety of a peptidyl arginine residue to investigate how changes to the PRMT substrate can modulate enzyme activity. We found that peptides bearing Nη-hydroxy or Nη-amino substituted arginine showed higher apparent kcat values than for the monomethylated substrate when using PRMT1, whereas this catalytic preference was not observed for PRMT4 and PRMT6. Methylation by compromised PRMT1 variants E153Q and D51N further supports the finding that the N-hydroxy substitution facilitates methyl transfer by tuning the reactivity of the guanidine moiety. In contrast, Nη-nitro and Nη-canavanine substituted substrates inhibit PRMT activity. These findings demonstrate that methylation of these PRMT substrates is dependent on the nature of the modification at the guanidine moiety.

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A Remodeled Protein Arginine Methyltransferase 1 (PRMT1) Generates Symmetric Dimethylarginine

Cited by 26 publications

References 39 publications

Histone H2A and H4 N-terminal Tails Are Positioned by the MEP50 WD Repeat Protein for Efficient Methylation by the PRMT5 Arginine Methyltransferase

Histone H2A and H4 N-terminal Tails Are Positioned by the MEP50 WD Repeat Protein for Efficient Methylation by the PRMT5 Arginine Methyltransferase

Kinetic Analysis of PRMT1 Reveals Multifactorial Processivity and a Sequential Ordered Mechanism

Protein Arginine N‐Methyltransferase Substrate Preferences for Different Nη‐Substituted Arginyl Peptides

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