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

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

doi:10.1074/jbc.m113.535278

Abstract

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 (ΔΔG(‡) = 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.

Highlights

Asymmetric and symmetric dimethylarginine (ADMA and SDMA) residues are biologically distinct products of protein arginine methyltransferase (PRMT) isoforms
M48F-protein arginine methyltransferase 1 (PRMT1) Generates asymmetric dimethylarginine (ADMA) and SDMA—Before the crystal structure of PRMT5 was solved, sequence alignment of Type I and II PRMTs indicated that the equivalent residue of Met-155 of PRMT1 in the Type II enzymes was a serine, a smaller amino acid
Following our previous studies on the product specificity of PRMT1 [13, 16], we further investigated how the PRMT1 active site discriminates between ADMA and SDMA

Summary

Introduction

Asymmetric and symmetric dimethylarginine (ADMA and SDMA) residues are biologically distinct products of protein arginine methyltransferase (PRMT) isoforms. 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. Protein arginine methylation is a major mechanism for regulating protein function in eukaryotic cells. 2 The abbreviations used are: PRMT, protein arginine methyltransferase; ADMA, asymmetric dimethylarginine; CID, collision-induced dissociation; ETD, electron transferring dissociation; AdoMet, S-adenosylmethionine; SDMA, symmetric dimethylarginine; MMA, monomethylarginine; QM, quantum mechanical; MM, molecular mechanical.

Results

Conclusion