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

作者：Gui Shanying; Gathiaka Symon; Li Jun; Qu Jun; Acevedo Orlando; Hevel Joan M^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(13): 9320-9327.

DOI：10.1074/jbc.M113.535278

• Computer Modeling
• Enzyme Mechanisms
• Histone Methylation
• Protein Methylation
• S-adenosylmethionine (SAM)
• Site-directed Mutagenesis
• Dimethylarginine
• Product Specificity
• Protein Arginine Methyltransferase

Background: Asymmetric and symmetric dimethylarginine (ADMA and SDMA) residues are biologically distinct products of protein arginine methyltransferase (PRMT) isoforms. Results: Met-48 in PRMT1 regulates the regiochemistry of dimethylation, and SDMA formation is energetically costly. Conclusion: Steric changes in the PRMT1 active site can reprogram product formation. Significance: SDMA-forming PRMTs may require additional factors to overcome the energetic cost of SDMA.
Protein arginine methylation is emerging as a significant post-translational modification involved in various cell processes and human diseases. As the major arginine methylation enzyme, protein arginine methyltransferase 1 (PRMT1) strictly generates monomethylarginine and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA). The two types of dimethylarginines can lead to distinct biological outputs, as highlighted in the PRMT-dependent epigenetic control of transcription. However, it remains unclear how PRMT1 product specificity is regulated. We discovered that a single amino acid mutation (Met-48 to Phe) in the PRMT1 active site enables PRMT1 to generate both ADMA and SDMA. Due to the limited amount of SDMA formed, we carried out quantum mechanical calculations to determine the free energies of activation of ADMA and SDMA synthesis. Our results indicate that the higher energy barrier of SDMA formation (G(double dagger) = 3.2 kcal/mol as compared with ADMA) may explain the small amount of SDMA generated by M48F-PRMT1. Our study reveals unique energetic challenges for SDMA-forming methyltransferases and highlights the exquisite control of product formation by active site residues in the PRMTs.

• 出版日期2014-3-28