2012年10月17日,，美國科學(xué)院院刊（Proceedings of the National Academy of Sciences）在線發(fā)表了生物大分子國家重點實驗室許瑞明、饒子和課題組和NIBS朱冰課題組合作的最新研究成果,，該文章題為Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1,。
組蛋白甲基化是表觀遺傳學(xué)的核心內(nèi)容之一，其中關(guān)于甲基化的識別是近年來研究的熱點,。甲基化識別蛋白是表觀遺傳信號的執(zhí)行者,，它們特異地識別不同位點、不同形式的甲基化修飾,，把信號傳遞給下游與其相互作用的分子,，行使表觀遺傳的生物學(xué)功能。許瑞明課題組基于前期基礎(chǔ)研究（Genes & Dev. 2003; Science 2006; Genes & Dev. 2009）,，此次在人源Spindlin1蛋白識別組蛋白H3第4位賴氨酸的三甲基化修飾（H3K4me3）研究中又取得了進一步成果,。
人源Spindlin1蛋白最早作為紡錘體結(jié)合蛋白被發(fā)現(xiàn)（Dev. 1997.）。2007年,，饒子和課題組解析了Spindlin1蛋白的三維晶體結(jié)構(gòu)（JBC 2007）,。2011年NIBS朱冰課題組發(fā)現(xiàn)Spindlin1定位在核內(nèi)活性rDNA重復(fù)區(qū)，可識別組蛋白H3K4甲基化修飾,，進而促進rDNA基因的表達（EMBO Reports 2011）?；谥暗难芯拷Y(jié)果,，許瑞明課題組與朱冰研究員和饒子和教授開展了Spindlin1與組蛋白H3K4me3識別的結(jié)構(gòu)機理研究。結(jié)果表明，Spindlin1包含三個串聯(lián)重復(fù)的Tudor結(jié)構(gòu)域,，其中只有Tudor II可以結(jié)合一個H3K4me3肽段,，通過結(jié)構(gòu)分析比較及體內(nèi)外功能實驗檢測，研究人員們發(fā)現(xiàn)了Spindlin1蛋白識別H3K4me3的獨特機制：首先,，可結(jié)合甲基化賴氨酸殘基的疏水口袋由4個芳香族殘基組成,，比其他已知的Tudor結(jié)構(gòu)域識別口袋都多了1個殘基，這樣的包圍的更加緊密,，同時對周圍的環(huán)境要求也更加苛刻,；其次，除了構(gòu)成疏水口袋的芳香族殘基,，Spindlin1的極性天冬氨酸殘基也與H3蛋白N端的精氨酸殘基有多處較強的相互作用,，分別對D184和D189殘基進行突變，不同程度的影響了Spindlin1與H3K4me3肽段的結(jié)合能力,，下調(diào)了體內(nèi)rRNA基因的轉(zhuǎn)錄水平,，這些極性相互作用確保了K4位點識別的特異性。（生物谷Bioon.com）
doi: 10.1073/pnas.1208517109
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Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1
Na Yang, Weixiang Wang, Yan Wang, Mingzhu Wang, Qiang Zhao, Zihe Rao, Bing Zhu and Rui-Ming Xu
Recognition of methylated histone tail lysine residues by tudor domains plays important roles in epigenetic control of gene expression and DNA damage response. Previous studies revealed the binding of methyllysine in a cage of aromatic residues, but the molecular mechanism by which the sequence specificity for surrounding histone tail residues is achieved remains poorly understood. In the crystal structure of a trimethylated histone H3 lysine 4 ( H3K4) peptide bound to the tudor - like domains of Spindlin1 presented here , anatypical mode of methyllysine recognition by an aromatic pocket of Spindlin1 is observed. Furthermore, the histone sequence is recognized in a distinct manner involving the amino terminus and a pair of arginine residues of histone H3, and disruption of the binding impaired stimulation of pre-RNA expression by Spindlin1. Our analysis demonstrates considerable diversities of methyllysine recognition and sequence-specific binding of histone tails by tudor domains, and the revel at ion furthers the under standing of tudor domain proteins in deciphering epigenetic marks on histone tails.
