12月5日,美国《国家科学院院刊》(PNAS) 在线发表了中科院生物物理研究所许瑞明、龚为民、刘迎芳研究组以及遗传发育所鲍时来课题组合作的最新研究成果Structural Insights into Protein Arginine Symmetric Dimethylation by PRMT5。
组蛋白甲基化是表观遗传学的核心内容之一,主要包括赖氨酸和精氨酸的甲基化修饰。相对于赖氨酸的单甲基、双甲基和三甲基化修饰,精氨酸也存在单甲基及双甲基化修饰。精氨酸双甲基化修饰中,对称性及非对称性修饰有着不同的生物学意义及识别机制。如针对组蛋白H4R3位点的双甲基化修饰中,对称修饰抑制基因表达,非对称修饰则与基因激活密切相关。但关于这两类修饰的反应机理,特别是对称性与非对称性修饰酶催化机制的差别还知之甚少。
这项新的研究工作解析了线虫精氨酸对称双甲基化酶PRMT5的晶体结构。根据已知的结构信息设计突变体实验,确定了PRMT5精氨酸甲基转移酶活性、特别是对称性双甲基化活性的关键残基,分析了PRMT5作为对称性双甲基化酶与其他非对称性双甲基化酶的结构差别。
这些结果对于理解精氨酸双甲基化修饰的作用机理及调控细节,具有重要意义。(生物谷Bioon.com)
doi:10.1073/pnas.1106946108
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Structural insights into protein arginine symmetric dimethylation by PRMT5
Litao Sun, Mingzhu Wang, Zongyang Lv, Na Yang, Yingfang Liu, Shilai Bao, Weimin Gong, and Rui-Ming Xu
Symmetric and asymmetric dimethylation of arginine are isomeric protein posttranslational modifications with distinct biological effects, evidenced by the methylation of arginine 3 of histone H4 (H4R3): symmetric dimethylation of H4R3 leads to repression of gene expression, while asymmetric dimethylation of H4R3 is associated with gene activation. The enzymes catalyzing these modifications share identifiable sequence similarities, but the relationship between their catalytic mechanisms is unknown. Here we analyzed the structure of a prototypic symmetric arginine dimethylase, PRMT5, and discovered that a conserved phenylalanine in the active site is critical for specifying symmetric addition of methyl groups. Changing it to a methionine significantly elevates the overall methylase activity, but also converts PRMT5 to an enzyme that catalyzes both symmetric and asymmetric dimethylation of arginine. Our results demonstrate a common catalytic mechanism intrinsic to both symmetric and asymmetric arginine dimethylases, and show that steric constrains in the active sites play an essential role in determining the product specificity of arginine methylases. This discovery also implies a potentially regulatable outcome of arginine dimethylation that may provide versatile control of eukaryotic gene expression.