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

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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
https://doi.org/10.1021/bi301283t
Copyright © 2012 American Chemical Society

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    Abstract

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    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.

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    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.

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    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 http://pubs.acs.org.

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