最近，美國加州理工大學(xué)的研究人員首次解開了一個長期存在的謎團(tuán),，即泛素(ubiquitin)如何在泛素連接酶(ubiquitin ligases)的協(xié)助下,，添加到控制細(xì)胞周期的特殊蛋白質(zhì)上。這項研究發(fā)表在本周的Nature雜志上,，或?qū)⒂兄陂_發(fā)治療癌癥的新方法,。
泛素是一種特殊的蛋白質(zhì)，主要功能是標(biāo)記需要被分解掉的蛋白質(zhì)上,，使其被水解,，標(biāo)記同一個靶蛋白往往需要4個或更多的泛素分子。在這項報告中,，課題組對泛素添加到靶蛋白cyclin E和β-Catenin泛素化的過程進(jìn)行研究,，這兩種靶蛋白能夠控制細(xì)胞的周期。
泛素標(biāo)記到被降解的蛋白質(zhì)上,，這一過程需要有三種不同的酶E1, E2和E3的參與,。簡而言之，即泛素活化酶E1激活泛素并將其轉(zhuǎn)移到泛素交聯(lián)酶E2上,，隨后泛素連接酶E3識別特定的需要被泛素化的靶蛋白,，并將泛素從E2上轉(zhuǎn)移到靶蛋白上,。
盡管科學(xué)家已經(jīng)了解了上述過程，但仍然存在一個問題：多個泛素鏈?zhǔn)且砸环N已裝配好的形式被轉(zhuǎn)移到靶蛋白上呢,，還是泛素鏈一個一個的轉(zhuǎn)移到靶蛋白上,？
為了解決這個問題，Pierce通過一種生物學(xué)停格動畫(biological stop-motion animation)進(jìn)行演示,，這種動畫每秒鐘可播放100幅圖片,，可以使研究人員觀察泛素從E2上轉(zhuǎn)移到cyclin E蛋白質(zhì)底物上的每一步驟。
當(dāng)然,，對泛素化過程的探究并不止于此,，研究人員將進(jìn)一步對泛素連接酶E3快速轉(zhuǎn)移泛素到靶蛋白上的分子機(jī)制進(jìn)行研究,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 462, 615-619 (3 December 2009) | doi:10.1038/nature08595
Detection of sequential polyubiquitylation on a millisecond timescale
Nathan W. Pierce1, Gary Kleiger1, Shu-ou Shan2,3 & Raymond J. Deshaies1,3
1 Howard Hughes Medical Institute, Division of Biology, MC 156-29,
2 Division of Chemistry and Chemical Engineering, MC 147-75, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA
3 These authors contributed equally to this work.
Correspondence to: Raymond J. Deshaies1,3 Correspondence and requests for materials should be addressed to R.J.D.
The pathway by which ubiquitin chains are generated on substrate through a cascade of enzymes consisting of an E1, E2 and E3 remains unclear. Multiple distinct models involving chain assembly on E2 or substrate have been proposed. However, the speed and complexity of the reaction have precluded direct experimental tests to distinguish between potential pathways. Here we introduce new theoretical and experimental methodologies to address both limitations. A quantitative framework based on product distribution predicts that the really interesting new gene (RING) E3 enzymes SCFCdc4 and SCF-TrCP work with the E2 Cdc34 to build polyubiquitin chains on substrates by sequential transfers of single ubiquitins. Measurements with millisecond time resolution directly demonstrate that substrate polyubiquitylation proceeds sequentially. Our results present an unprecedented glimpse into the mechanism of RING ubiquitin ligases and illuminate the quantitative parameters that underlie the rate and pattern of ubiquitin chain assembly.
