Protein arginine methyltransferases (PRMTs) are important post-translational modifying enzymes in eukaryotic proteins and regulate diverse pathways from gene transcription, RNA splicing, and signal transduction to metabolism. Increasing evidence supports that PRMTs exhibit the capacity to form higher-order oligomeric structures, but the structural basis of PRMT oligomerization and its functional consequence are elusive. Herein, we revealed for the first time different oligomeric structural forms of the predominant arginine methyltransferase PRMT1 using cryogenic electron microscopy, which included tetramer (dimer of dimers), hexamer (trimer of dimers), octamer (tetramer of dimers), decamer (pentamer of dimers), and also helical filaments. Through a host of biochemical assays, we showed that PRMT1 methyltransferase activity was substantially enhanced as a result of the high-ordered oligomerization. High-ordered oligomerization increased the catalytic turnover and the multi-methylation processivity of PRMT1. Presence of a catalytically-dead PRMT1 mutant also abled enhanced activity of wild-type PRMT1, pointing out a non-catalytic role of oligomerization. Structural modeling demonstrates that oligomerization enhances substrate retention at the PRMT1 surface through electrostatic force. Our studies offered key insights into PRMT1 oligomerization and established that oligomerization constitutes a novel molecular mechanism that positively regulates the enzymatic activity of PRMTs in biology.

中文翻译：

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蛋白精氨酸甲基转移酶 1 的寡聚化及其对底物精氨酸甲基化的功能影响。


蛋白精氨酸甲基转移酶 （PRMTs） 是真核蛋白中重要的翻译后修饰酶，可调节从基因转录、RNA 剪接和信号转导到代谢的不同途径。越来越多的证据支持 PRMT 表现出形成高阶寡聚结构的能力，但 PRMT 寡聚化的结构基础及其功能后果难以捉摸。在此，我们首次使用低温电子显微镜揭示了主要精氨酸甲基转移酶 PRMT1 的不同寡聚体结构形式，其中包括四聚体（二聚体的二聚体）、六聚体（二聚体的三聚体）、八聚体（二聚体的四聚体）、十聚体（二聚体的五聚体）以及螺旋丝。通过一系列生化分析，我们表明由于高阶寡聚化，PRMT1 甲基转移酶活性显着增强。高有序寡聚化增加了 PRMT1 的催化周转和多甲基化持续合成能力。催化死亡 PRMT1 突变体的存在也能够增强野生型 PRMT1 的活性，指出寡聚化的非催化作用。结构建模表明，寡聚化通过静电力增强了 PRMT1 表面的底物保留。我们的研究为 PRMT1 寡聚化提供了关键见解，并确定寡聚化构成了一种新的分子机制，可积极调节生物学中 PRMT 的酶活性。