12月5日，美國《國家科學(xué)院院刊》(PNAS) 在線發(fā)表了中科院生物物理研究所許瑞明,、龔為民,、劉迎芳研究組以及遺傳發(fā)育所鮑時來課題組合作的最新研究成果Structural Insights into Protein Arginine Symmetric Dimethylation by PRMT5。
組蛋白甲基化是表觀遺傳學(xué)的核心內(nèi)容之一,，主要包括賴氨酸和精氨酸的甲基化修飾,。相對于賴氨酸的單甲基、雙甲基和三甲基化修飾,，精氨酸也存在單甲基及雙甲基化修飾,。精氨酸雙甲基化修飾中，對稱性及非對稱性修飾有著不同的生物學(xué)意義及識別機制,。如針對組蛋白H4R3位點的雙甲基化修飾中,，對稱修飾抑制基因表達(dá)，非對稱修飾則與基因激活密切相關(guān),。但關(guān)于這兩類修飾的反應(yīng)機理,，特別是對稱性與非對稱性修飾酶催化機制的差別還知之甚少。
這項新的研究工作解析了線蟲精氨酸對稱雙甲基化酶PRMT5的晶體結(jié)構(gòu),。根據(jù)已知的結(jié)構(gòu)信息設(shè)計突變體實驗,，確定了PRMT5精氨酸甲基轉(zhuǎn)移酶活性、特別是對稱性雙甲基化活性的關(guān)鍵殘基,，分析了PRMT5作為對稱性雙甲基化酶與其他非對稱性雙甲基化酶的結(jié)構(gòu)差別,。
這些結(jié)果對于理解精氨酸雙甲基化修飾的作用機理及調(diào)控細(xì)節(jié)，具有重要意義,。（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.
