Jin Cyrus Y, Hunkeler Moritz, Mulvaney Kathleen M, Sellers William R, Fischer Eric S
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
Fralin Biomedical Research Institute, Virginia Tech FBRI Cancer Research Center, Washington, District of Columbia, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
J Biol Chem. 2025 Feb;301(2):108165. doi: 10.1016/j.jbc.2025.108165. Epub 2025 Jan 8.
Protein arginine methyltransferase (PRMT) 5 is an essential arginine methyltransferase responsible for the majority of cellular symmetric dimethyl-arginine marks. PRMT5 uses substrate adaptors such as pICln, RIOK1, and COPR5 to recruit and methylate a wide range of substrates. Although the substrate adaptors play important roles in substrate recognition, how they direct PRMT5 activity towards specific substrates remains incompletely understood. Using biochemistry and cryogenic electron microscopy, we show that these adaptors compete for the same binding site on PRMT5. We find that substrate adaptor and substrate complexes are bound to PRMT5 through two peptide motifs, enabling these adaptors to act as flexible tethering modules to enhance substrate methylation. Taken together, our results shed structural and mechanistic light on the PRMT5 substrate adaptor function and the biochemical nature of PRMT5 interactors.
蛋白质精氨酸甲基转移酶（PRMT）5是一种重要的精氨酸甲基转移酶，负责细胞中大部分对称二甲基精氨酸标记。PRMT5利用诸如pICln、RIOK1和COPR5等底物衔接蛋白来招募并甲基化多种底物。尽管底物衔接蛋白在底物识别中发挥重要作用，但它们如何将PRMT5的活性导向特定底物仍未完全明确。通过生物化学和低温电子显微镜技术，我们发现这些衔接蛋白竞争PRMT5上的同一结合位点。我们还发现底物衔接蛋白和底物复合物通过两个肽基序与PRMT5结合，这使得这些衔接蛋白能够作为灵活的拴系模块来增强底物甲基化。综上所述，我们的研究结果为PRMT5底物衔接蛋白的功能以及PRMT5相互作用分子的生化特性提供了结构和机制方面的见解。
