Maron Maxim I, Lehman Stephanie M, Gayatri Sitaram, DeAngelo Joseph D, Hegde Subray, Lorton Benjamin M, Sun Yan, Bai Dina L, Sidoli Simone, Gupta Varun, Marunde Matthew R, Bone James R, Sun Zu-Wen, Bedford Mark T, Shabanowitz Jeffrey, Chen Hongshan, Hunt Donald F, Shechter David
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
iScience. 2021 Aug 11;24(9):102971. doi: 10.1016/j.isci.2021.102971. eCollection 2021 Sep 24.
Protein arginine methyltransferases (PRMTs) catalyze the post-translational monomethylation (Rme1), asymmetric (Rme2a), or symmetric (Rme2s) dimethylation of arginine. To determine the cellular consequences of type I (Rme2a) and II (Rme2s) PRMTs, we developed and integrated multiple approaches. First, we determined total cellular dimethylarginine levels, revealing that Rme2s was ∼3% of total Rme2 and that this percentage was dependent upon cell type and PRMT inhibition status. Second, we quantitatively characterized substrates of the major enzymes and expanded upon PRMT substrate recognition motifs. We also compiled our data with publicly available methylarginine-modified residues into a comprehensive database. Third, we inhibited type I and II PRMTs and performed proteomic and transcriptomic analyses to reveal their phenotypic consequences. These experiments revealed both overlapping and independent PRMT substrates and cellular functions. Overall, this study expands upon PRMT substrate diversity, the arginine methylome, and the complex interplay of type I and II PRMTs.
蛋白质精氨酸甲基转移酶（PRMTs）催化精氨酸的翻译后单甲基化（Rme1）、不对称二甲基化（Rme2a）或对称二甲基化（Rme2s）。为了确定I型（Rme2a）和II型（Rme2s）PRMTs的细胞效应，我们开发并整合了多种方法。首先，我们测定了细胞内二甲基精氨酸的总水平，发现Rme2s占总Rme2的3%左右，且该百分比取决于细胞类型和PRMT抑制状态。其次，我们对主要酶的底物进行了定量表征，并扩展了PRMT底物识别基序。我们还将自己的数据与公开可用的甲基精氨酸修饰残基数据整合到一个综合数据库中。第三，我们抑制I型和II型PRMTs，并进行蛋白质组学和转录组学分析以揭示其表型效应。这些实验揭示了PRMTs的重叠和独立底物以及细胞功能。总体而言，本研究扩展了PRMT底物多样性、精氨酸甲基化组以及I型和II型PRMTs之间的复杂相互作用。
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