近期,，國(guó)際著名學(xué)術(shù)期刊PNAS在線發(fā)表了中國(guó)科學(xué)技術(shù)大學(xué)生命科學(xué)學(xué)院施蘊(yùn)渝教授與姚雪彪教授研究組的合作成果,。文章標(biāo)題為EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore-microtubule interactions in mitosis。該成果揭示了微管正端示蹤蛋白EB1被乙?；窹CAF修飾并精細(xì)調(diào)控細(xì)胞有絲分裂染色體著絲粒（動(dòng)點(diǎn)）與微管連接的分子機(jī)制,。文章第一作者為中國(guó)科學(xué)技術(shù)大學(xué)生命科學(xué)院博士生夏鵬和王志凱。
有絲分裂順利完成依賴于雙極紡錘體的形成以及染色體沿紡錘體微管軌道的精確移動(dòng),。染色體通過(guò)著絲粒尋找以及捕獲紡錘體微管正末端,，在這一過(guò)程中，微管正端示蹤蛋白超家族具有至關(guān)重要的作用,。在有絲分裂過(guò)程中,，微管末端結(jié)合蛋白1（End-binding protein 1, EB1)作為微管正端示蹤蛋白超家族的核心分子，定位于動(dòng)點(diǎn)與微管連接處,，并招募和調(diào)控微管正端示蹤蛋白超家族在動(dòng)點(diǎn)-微管連接中行使功能,。利用結(jié)構(gòu)生物學(xué)引導(dǎo)的功能分析法，本項(xiàng)研究成果證明著絲粒相關(guān)的乙?；窹CAF特異性地對(duì)EB1的220位賴氨酸進(jìn)行乙?；揎棧M(jìn)而影響到EB1分子中一個(gè)疏水窩狀結(jié)構(gòu)的穩(wěn)定性,，而這個(gè)疏水窩正是介導(dǎo)其他微管示蹤蛋白結(jié)合EB1分子的關(guān)鍵部分,。進(jìn)而該乙酰化修飾會(huì)影響整個(gè)微管示蹤蛋白超復(fù)合物的組裝,。同時(shí),，EB1的220位賴氨酸乙酰化特異性識(shí)別抗體揭示該乙?；揎椝皆诩?xì)胞進(jìn)入有絲分裂期時(shí)有增高趨勢(shì),。表達(dá)模擬乙酰化突變體EB1的細(xì)胞在有絲分裂中期染色體排列在赤道板時(shí)出現(xiàn)延遲,，并使得有絲分裂中期檢驗(yàn)點(diǎn)持續(xù)激活,。該項(xiàng)研究首次發(fā)現(xiàn)翻譯后修飾對(duì)于微管正端示蹤蛋白超復(fù)合物組裝的時(shí)空動(dòng)力學(xué)調(diào)控，并通過(guò)這種調(diào)控影響和控制染色體著絲粒與微管之間的連接,。該調(diào)控機(jī)制的闡明對(duì)于理解有絲分裂精密調(diào)控具有重大意義,，并為阻斷癌癥細(xì)胞增殖提供了新的靶點(diǎn)。（生物谷Bioon.com）
doi: 10.1073/pnas.1202639109
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EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore–microtubule interactions in mitosis
Peng Xia, Zhikai Wang, Xing Liu, Bing Wu, Juncheng Wang, Tarsha Ward, Liangyu Zhang, Xia Ding, Gary Gibbons, Yunyu Shi, and Xuebiao Yao
In eukaryotes, microtubules are essential for cellular plasticity and dynamics. Here we show that P300/CBP-associated factor (PCAF), a kinetochore-associated acetyltransferase, acts as a negative modulator of microtubule stability through acetylation of EB1, a protein that controls the plus ends of microtubules. PCAF acetylates EB1 on K220 and disrupts the stability of a hydrophobic cavity on the dimerized EB1 C terminus, which was previously reported to interact with plus-end tracking proteins (TIPs) containing the SxIP motif. As determined with an EB1 acetyl-K220–specific antibody, K220 acetylation is dramatically increased in mitosis and localized to the spindle microtubule plus ends. Surprisingly, persistent acetylation of EB1 delays metaphase alignment, resulting in impaired checkpoint silencing. Consequently, suppression of Mad2 overrides mitotic arrest induced by persistent EB1 acetylation. Thus, our findings identify dynamic acetylation of EB1 as a molecular mechanism to orchestrate accurate kinetochore–microtubule interactions in mitosis. These results establish a previously uncharacterized regulatory mechanism governing localization of microtubule plus-end tracking proteins and thereby the plasticity and dynamics of cells.
