2012年10月17日，美國(guó)科學(xué)院院刊（Proceedings of the National Academy of Sciences）在線(xiàn)發(fā)表了生物大分子國(guó)家重點(diǎn)實(shí)驗(yàn)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(guān)遺傳學(xué)的核心內(nèi)容之一,，其中關(guān)于甲基化的識(shí)別是近年來(lái)研究的熱點(diǎn)。甲基化識(shí)別蛋白是表觀(guān)遺傳信號(hào)的執(zhí)行者,，它們特異地識(shí)別不同位點(diǎn),、不同形式的甲基化修飾，把信號(hào)傳遞給下游與其相互作用的分子，行使表觀(guān)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(shí)別組蛋白H3第4位賴(lài)氨酸的三甲基化修飾（H3K4me3）研究中又取得了進(jìn)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(shí)別組蛋白H3K4甲基化修飾,，進(jìn)而促進(jìn)rDNA基因的表達(dá)（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(kāi)展了Spindlin1與組蛋白H3K4me3識(shí)別的結(jié)構(gòu)機(jī)理研究。結(jié)果表明,，Spindlin1包含三個(gè)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(gè)H3K4me3肽段，通過(guò)結(jié)構(gòu)分析比較及體內(nèi)外功能實(shí)驗(yàn)檢測(cè),，研究人員們發(fā)現(xiàn)了Spindlin1蛋白識(shí)別H3K4me3的獨(dú)特機(jī)制：首先,，可結(jié)合甲基化賴(lài)氨酸殘基的疏水口袋由4個(gè)芳香族殘基組成，比其他已知的Tudor結(jié)構(gòu)域識(shí)別口袋都多了1個(gè)殘基,，這樣的包圍的更加緊密,，同時(shí)對(duì)周?chē)沫h(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(qiáng)的相互作用，分別對(duì)D184和D189殘基進(jìn)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(diǎn)識(shí)別的特異性,。（生物谷Bioon.com）
doi: 10.1073/pnas.1208517109
PMC:
PMID:
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.
