ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Substrate-Induced Control of Product Formation by Protein Arginine Methyltransferase 1

View Author Information
Chemistry and Biochemistry Department, Utah State University, 0300 Old Main Hill, Logan, Utah 84322, United States
The Barnett Institute of Chemical and Biological Analysis, Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115-5000, United States
§ Synthetic Bio-manufacturing Institute, Utah State University, 620 East 1600 North, Suite 226, Logan, Utah 84341, United States
Waters Corporation, 100 Cummings Center, Suite 407N, Beverly, Massachusetts 01915, United States
*Chemistry and Biochemistry Department, Utah State University, 0300 Old Main Hill, Logan, UT 84322. Telephone: (435) 797-1622. Fax: (435) 797-3390. E-mail: [email protected]
Cite this: Biochemistry 2013, 52, 1, 199–209
Publication Date (Web):December 10, 2012
Copyright © 2012 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    Abstract Image

    Protein arginine methyltransferases (PRMTs) aid in the regulation of many biological processes. Accurate control of PRMT activity includes recognition of specific arginyl groups within targeted proteins and the generation of the correct level of methylation, none of which are fully understood. The predominant PRMT in vivo, PRMT1, has wide substrate specificity and is capable of both mono- and dimethylation, which can induce distinct biological outputs. What regulates the specific methylation pattern of PRMT1 in vivo is unclear. We report that PRMT1 methylates a multisite peptide substrate in a nonstochastic manner, with less C-terminal preference, consistent with the methylation patterns observed in vivo. With a single targeted arginine, PRMT1 catalyzed the dimethylation in a semiprocessive manner. The degree of processivity is regulated by substrate sequences. Our results identify a novel substrate-induced mechanism for modulating PRMT1 product specificity. Considering the numerous physiological PRMT1 substrates, as well as the distinct biological outputs of mono- and dimethylation products, such fine-tuned regulation would significantly contribute to the accurate product specificity of PRMT1 in vivo and the proper transmission of biochemical information.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Bold and underlined arginine residues (R) are methylation sites of PRMT1.

    Approximations assume that the small difference observed in kcat/Km between the naked and monomethylated peptide substrates in the steady state does not alter product partitioning by an appreciable amount in the double-turnover experiments.

    Supporting Information

    Jump To

    MS and LC–MS/MS analyses of methylation order in multi-arginine-containing peptide substrates and steady-state kinetic study and intrinsic fluorescence quenching results for the single-arginine-containing peptides. This material is available free of charge via the Internet at

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 39 publications.

    1. Wan-Sheng Ren, Kai-Bin Jiang, Hao Deng, Nan Lu, Tao Yu, Hong Guo, Ping Qian. Catalytic Mechanism and Product Specificity of Protein Arginine Methyltransferase PRMT7: A Study from QM/MM Molecular Dynamics and Free Energy Simulations. Journal of Chemical Theory and Computation 2020, 16 (8) , 5301-5312.
    2. Abhishek Thakur, Joan M. Hevel, Orlando Acevedo. Examining Product Specificity in Protein Arginine Methyltransferase 7 (PRMT7) Using Quantum and Molecular Mechanical Simulations. Journal of Chemical Information and Modeling 2019, 59 (6) , 2913-2923.
    3. Suzanne L. Jacques, Katrina P. Aquino, Jodi Gureasko, P. Ann Boriack-Sjodin, Margaret Porter Scott, Robert A. Copeland, and Thomas V. Riera . CARM1 Preferentially Methylates H3R17 over H3R26 through a Random Kinetic Mechanism. Biochemistry 2016, 55 (11) , 1635-1644.
    4. Jakob Fuhrmann and Paul R. Thompson . Protein Arginine Methylation and Citrullination in Epigenetic Regulation. ACS Chemical Biology 2016, 11 (3) , 654-668.
    5. Wanlu Qu, Kalli C. Catcott, Kun Zhang, Shanshan Liu, Jason J. Guo, Jisheng Ma, Michael Pablo, James Glick, Yuan Xiu, Nathaniel Kenton, Xiaoyu Ma, Richard I. Duclos, Jr., and Zhaohui Sunny Zhou . Capturing Unknown Substrates via in Situ Formation of Tightly Bound Bisubstrate Adducts: S-Adenosyl-vinthionine as a Functional Probe for AdoMet-Dependent Methyltransferases. Journal of the American Chemical Society 2016, 138 (9) , 2877-2880.
    6. Chris Chumsae, Patrick Hossler, Haly Raharimampionona, Yu Zhou, Sean McDermott, Chris Racicot, Czeslaw Radziejewski, and Zhaohui Sunny Zhou . When Good Intentions Go Awry: Modification of a Recombinant Monoclonal Antibody in Chemically Defined Cell Culture by Xylosone, an Oxidative Product of Ascorbic Acid. Analytical Chemistry 2015, 87 (15) , 7529-7534.
    7. Jakob Fuhrmann, Kathleen W. Clancy, and Paul R. Thompson . Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation. Chemical Reviews 2015, 115 (11) , 5413-5461.
    8. Min Wang, Jakob Fuhrmann, and Paul R. Thompson . Protein Arginine Methyltransferase 5 Catalyzes Substrate Dimethylation in a Distributive Fashion. Biochemistry 2014, 53 (50) , 7884-7892.
    9. Chris Chumsae, Liqiang Lisa Zhou, Yang Shen, Jessica Wohlgemuth, Emma Fung, Randall Burton, Czeslaw Radziejewski, and Zhaohui Sunny Zhou . Discovery of a Chemical Modification by Citric Acid in a Recombinant Monoclonal Antibody. Analytical Chemistry 2014, 86 (18) , 8932-8936.
    10. Leilei Yan, Chunli Yan, Kun Qian, Hairui Su, Stephanie A. Kofsky-Wofford, Wei-Chao Lee, Xinyang Zhao, Meng-Chiao Ho, Ivaylo Ivanov, and Yujun George Zheng . Diamidine Compounds for Selective Inhibition of Protein Arginine Methyltransferase 1. Journal of Medicinal Chemistry 2014, 57 (6) , 2611-2622.
    11. Min Wang, Rui-Ming Xu, and Paul R. Thompson . Substrate Specificity, Processivity, and Kinetic Mechanism of Protein Arginine Methyltransferase 5. Biochemistry 2013, 52 (32) , 5430-5440.
    12. Ashley K. Alexander, Sherif I. Elshahawi. Promiscuous Enzymes for Residue‐Specific Peptide and Protein Late‐Stage Functionalization. ChemBioChem 2023, 24 (17)
    13. Melody D. Fulton, Tran Dang, Tyler Brown, Y. George Zheng. Effects of substrate modifications on the arginine dimethylation activities of PRMT1 and PRMT5. Epigenetics 2022, 17 (1) , 1-18.
    14. Owen M. Price, Abhishek Thakur, Ariana Ortolano, Arianna Towne, Caroline Velez, Orlando Acevedo, Joan M. Hevel. Naturally occurring cancer-associated mutations disrupt oligomerization and activity of protein arginine methyltransferase 1 (PRMT1). Journal of Biological Chemistry 2021, 297 (5) , 101336.
    15. Charlène Thiebaut, Louisane Eve, Coralie Poulard, Muriel Le Romancer. Structure, Activity, and Function of PRMT1. Life 2021, 11 (11) , 1147.
    16. Maxim I. Maron, Stephanie M. Lehman, Sitaram Gayatri, Joseph D. DeAngelo, Subray Hegde, Benjamin M. Lorton, Yan Sun, Dina L. Bai, Simone Sidoli, Varun Gupta, Matthew R. Marunde, James R. Bone, Zu-Wen Sun, Mark T. Bedford, Jeffrey Shabanowitz, Hongshan Chen, Donald F. Hunt, David Shechter. Independent transcriptomic and proteomic regulation by type I and II protein arginine methyltransferases. iScience 2021, 24 (9) , 102971.
    17. Joan M. Hevel, Owen M. Price. Rapid and direct measurement of methyltransferase activity in about 30 min. Methods 2020, 175 , 3-9.
    18. Jennifer I. Brown, Brent D.G. Page, Adam Frankel. The application of differential scanning fluorimetry in exploring bisubstrate binding to protein arginine N-methyltransferase 1. Methods 2020, 175 , 10-23.
    19. Na Li, Feng Yao, Huifang Huang, Hong Zhang, Wan Zhang, Xiangyang Zou, Linlin Sui, Lin Hou. The potential role of Annexin 3 in diapause embryo restart of Artemia sinica and in response to stress of low temperature. Molecular Reproduction and Development 2019, 86 (5) , 530-542.
    20. Adam Frankel, Jennifer I. Brown. Evaluation of kinetic data: What the numbers tell us about PRMTs. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 2019, 1867 (3) , 306-316.
    21. Melody D. Fulton, Tyler Brown, Y. George Zheng. Mechanisms and Inhibitors of Histone Arginine Methylation. The Chemical Record 2018, 18 (12) , 1792-1807.
    22. Jonathan Woodsmith, Victoria Casado-Medrano, Nouhad Benlasfer, Rebecca L Eccles, Saskia Hutten, Christian L Heine, Verena Thormann, Claudia Abou-Ajram, Oliver Rocks, Dorothee Dormann, Ulrich Stelzl. Interaction modulation through arrays of clustered methyl-arginine protein modifications. Life Science Alliance 2018, 1 (5) , e201800178.
    23. Jennifer I. Brown, Timo Koopmans, Jolinde van Strien, Nathaniel I. Martin, Adam Frankel. Kinetic Analysis of PRMT1 Reveals Multifactorial Processivity and a Sequential Ordered Mechanism. ChemBioChem 2018, 19 (1) , 85-99.
    24. Akihiko Kanou, Koichiro Kako, Keiko Hirota, Akiyoshi Fukamizu. PRMT-5 converts monomethylarginines into symmetrical dimethylarginines in Caenorhabditis elegans. The Journal of Biochemistry 2017, 161 (2) , 231-235.
    25. Hao Hu, Cheng Luo, Y. George Zheng. Transient Kinetics Define a Complete Kinetic Model for Protein Arginine Methyltransferase 1. Journal of Biological Chemistry 2016, 291 (52) , 26722-26738.
    26. Symon Gathiaka, Brittany Boykin, Tamar Cáceres, Joan M. Hevel, Orlando Acevedo. Understanding protein arginine methyltransferase 1 (PRMT1) product specificity from molecular dynamics. Bioorganic & Medicinal Chemistry 2016, 24 (20) , 4949-4960.
    27. Tianzhu Zang, Ligi Pottenplackel, Diane Handy, Joseph Loscalzo, Shujia Dai, Richard Deth, Zhaohui Zhou, Jisheng Ma. Comparison of Protein N-Homocysteinylation in Rat Plasma under Elevated Homocysteine Using a Specific Chemical Labeling Method. Molecules 2016, 21 (9) , 1195.
    28. Shanshan Liu, Kevin Ryan Moulton, Jared Robert Auclair, Zhaohui Sunny Zhou. Mildly acidic conditions eliminate deamidation artifact during proteolysis: digestion with endoprotease Glu-C at pH 4.5. Amino Acids 2016, 48 (4) , 1059-1067.
    29. Kun Qian, Y. George Zheng. Current Development of Protein Arginine Methyltransferase Inhibitors. 2016, 231-256.
    30. Yalemi Morales, Tamar Cáceres, Kyle May, Joan M. Hevel. Biochemistry and regulation of the protein arginine methyltransferases (PRMTs). Archives of Biochemistry and Biophysics 2016, 590 , 138-152.
    31. Luc Bonnefond, Johann Stojko, Justine Mailliot, Nathalie Troffer-Charlier, Vincent Cura, Jean-Marie Wurtz, Sarah Cianférani, Jean Cavarelli. Functional insights from high resolution structures of mouse protein arginine methyltransferase 6. Journal of Structural Biology 2015, 191 (2) , 175-183.
    32. Xue Jiang, Feng Yao, Xuejie Li, Baolin Jia, Guangying Zhong, Jianfeng Zhang, Xiangyang Zou, Lin Hou. Molecular cloning, characterization and expression analysis of the protein arginine N-methyltransferase 1 gene (As-PRMT1) from Artemia sinica. Gene 2015, 565 (1) , 122-129.
    33. Andrea Hadjikyriacou, Yanzhong Yang, Alexsandra Espejo, Mark T. Bedford, Steven G. Clarke. Unique Features of Human Protein Arginine Methyltransferase 9 (PRMT9) and Its Substrate RNA Splicing Factor SF3B2. Journal of Biological Chemistry 2015, 290 (27) , 16723-16743.
    34. Richard I. Duclos, Dillon C. Cleary, Kalli C. Catcott, Zhaohui Sunny Zhou. Synthesis and characterization of Se -adenosyl-L-selenohomocysteine selenoxide. Journal of Sulfur Chemistry 2015, 36 (2) , 135-144.
    35. Joshua J. Klaene, Wenqin Ni, Joshua F. Alfaro, Zhaohui Sunny Zhou. Detection and Quantitation of Succinimide in Intact Protein via Hydrazine Trapping and Chemical Derivatization. Journal of Pharmaceutical Sciences 2014, 103 (10) , 3033-3042.
    36. Vincent Cura, Nathalie Troffer-Charlier, Jean-Marie Wurtz, Luc Bonnefond, Jean Cavarelli. Structural insight into arginine methylation by the mouse protein arginine methyltransferase 7: a zinc finger freezes the mimic of the dimeric state into a single active site. Acta Crystallographica Section D Biological Crystallography 2014, 70 (9) , 2401-2412.
    37. Shanying Gui, Symon Gathiaka, Jun Li, Jun Qu, Orlando Acevedo, Joan M. Hevel. A Remodeled Protein Arginine Methyltransferase 1 (PRMT1) Generates Symmetric Dimethylarginine. Journal of Biological Chemistry 2014, 289 (13) , 9320-9327.
    38. Mynol Vhuiyan, Dylan Thomas, Farhad Hossen, Adam Frankel. Targeting protein arginine N -methyltransferases with peptide-based inhibitors: opportunities and challenges. Future Medicinal Chemistry 2013, 5 (18) , 2199-2206.
    39. Ruihan Zhang, Xin Li, Zhongjie Liang, Kongkai Zhu, Junyan Lu, Xiangqian Kong, Sisheng Ouyang, Lin Li, Yujun George Zheng, Cheng Luo, . Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1. PLoS ONE 2013, 8 (8) , e72424.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect